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    [Compare of laparoscopic and open surgery for radical cystectomy with orthotopic ileal neobladder]. Huang Jian,Huang Hai,Lin Tian-xin,Xu Ke-wei,Zhang Cai-xia,Guo Zheng-hui,Jiang Chun,Yin Xin-bao,Han Jin-li,Yao You-sheng,Xie Wen-lian Zhonghua wai ke za zhi [Chinese journal of surgery] OBJECTIVE:To compare the clinical therapeutic effect and complications of laparoscopic radical cystectomy with orthotopic ileal neobladder (LRC-INB) with open radical cystectomy with orthotopic ileal neobladder (ORC-INB). METHODS:A total of 171 patients were evaluated, including 63 cases with ORC-INB and 108 cases with LRC-INB from June 1994 to May 2007 at our institution. The parameters analyzed included perioperative data, postoperative complications, new bladder function and effect of tumor control. RESULTS:There was no significant difference in demographic characteristics of patients between these 2 groups. The mean operating time was 330 min in the LRC group and 310 min in the ORC group (P > 0.05). The mean blood loss was 320 ml in the LRC group and 1100 ml in ORC group (P < 0.001). The mean oral intake after operation was 2.4 days for LRC group and 4.5 days for ORC group (P < 0.001). No perioperative death was occurred in both groups. The complication rate was 18.5% in LRC group, while 30.0% in ORC group (P < 0.05). Twelve months after operation, the day-time and night-time continence rate were 90.7% and 82.6% for the LRC group, 88.3% and 81.6% for the ORC group respectively (P > 0.05). There was no significant difference of VOL, pressure and residual urine volume (RUV) of neobladder between these 2 groups. Surgical margin were tumor free for 107 cases except one T4 case in laparoscopic group had positive margin (P > 0.05). The mean number of removed lymph node were 12 and 8 in LRC and ORC group respectively (P < 0.05). The 2 years tumor free survival rate of the same stage or grade was no significant different (P > 0.05). CONCLUSIONS:LCR had advantages of less blood loss, shorter oral intake time, less postoperative complications, comparable continent rate and short-term tumor control with ORC. Long-term follow up is needed to confirm the oncological outcome.
    Laparoscopic radical cystectomy with orthotopic ileal neobladder in the female: report of 14 cases. Lin Tian-xin,Zhang Cai-xia,Xu Ke-wei,Huang Hai,Jiang Chun,Han Jin-li,Yao You-sheng,Guo Zheng-hui,Xie Wen-lian,Yin Xin-bao,Huang Jian Chinese medical journal BACKGROUND:Bladder carcinoma is the most common malignant urological tumor in China. We present our preliminary experience and results of laparoscopic radical cystectomy (LRC) with orthotopic ileal neobladder in female patients with bladder carcinoma. METHODS:From February 2003 to February 2008, 14 female patients with bladder carcinoma underwent LRC with orthotopic ileal neobladder. Nine of these patients underwent hysterectomy and ovariectomy, and the other 5 had preservation of the uterus and ovarian appendage. Standard bilateral pelvic lymphadenectomy was followed by radical cystectomy that was completed laparoscopically with hysterectomy and ovariectomy when needed. The tumor was removed by a 4 - 5 cm lower midline abdominal incision, followed by the construction of ileal neobladder and the extracorporeal anastomosis of ureter-neobladder. The neobladder was anastomosed to the urethral stump under a laparoscope. RESULTS:The mean operative time and blood loss in the 14 patients were 350.2 minutes and 349.8 ml, respectively. Postoperative complications included uretero-pouch anastomotic stricture in 1 patient and pouch-vaginal fistula in 1 patient. Follow-up time of all patients ranged from 3 to 60 months, and 12 patients were followed up for more than 6 months and achieved micturition in half a year. One patient had occasional day-time urinary incontinence and 2 had night-time incontinence. Two patients who had undergone hysterectomy and ovariectomy had voiding difficulties after one year, which was treated by intermittent self-catheterization. The mean volume of the neobladder and the residual urine were 333.6 ml and 31.2 ml, respectively. Surgical margins were tumor free for all patients. One patient had bone metastasis and died 11 months after the operation. CONCLUSIONS:LRC with orthotopic ileal neobladder in female patients is a technically feasible, safe and mini-invasive procedure with a low morbidity and acceptable neobladder function. Long-term follow-up is required to confirm the neobladder function and oncological outcomes.
    [Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression in superficial transitional cell bladder carcinoma]. Guo Zheng-Hui,Mei Hua,Huang Jian,Li Si-Yao Ai zheng = Aizheng = Chinese journal of cancer BACKGROUND & OBJECTIVE:Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) can promote the proliferation of endothelial cell and angiogenesis. They are important materials in growth, invasion, and metastasis of tumor. There were few reports of their difference in single and multiple superficial transitional cell bladder carcinoma. Our objective was to study the expression of them in single and multiple superficial transitional cell bladder carcinoma and their clinical significance. METHODS:Immunohistochemical method was used to study the VEGF and bFGF expression in 60 cases of superficial transitional cell bladder carcinoma and in 10 cases of normal bladder tissue (as control). RESULTS:The expression levels of VEGF (55.6%), bFGF (50.0%), and coexpression level of VEGF and bFGF (50.0%) in the multiple superficial transitional cell bladder carcinoma were higher than that in single tumor. The recurrent rate in the patients with VEGF high expression (61.1%) was higher than that in the patients with VEGF low expression (16.7%). CONCLUSION:The expression levels of VEGF and bFGF were correlated with the biological behavior of superficial transitional cell bladder carcinoma.
    Microlocalization and clinical significance of stabilin-1 macrophages in treatment-naïve patients with urothelial carcinoma of the bladder. Wang Bo,Huang Hao,Yang Meihua,Yang Wenjuan,Liu Zhuowei,Hou Weibin,Zeng Hong,He Zhihua,Lin Tianxin,Huang Jian World journal of urology PURPOSE:Emerging evidence has shown that macrophages (Mφs) at different tumor sites have diverse clinical attributes. Stabilin-1 is a multi-functional scavenger marker for specialized tumor-associated Mφs. This study investigates the relationship between the density and microlocalization of stabilin-1 Mφs within tumors and the clinical outcomes of patients with urothelial carcinoma of the bladder (UCB). METHODS:In this retrospective study, 283 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry and immunofluorescence analyses were used to colocalize the expression of stabilin-1 with other markers for Mφs (CD14, CD68, CD163, and CD206). Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival (OS) and recurrence-free survival (RFS). RESULTS:In UCB tissues, stabilin-1 was primarily expressed on Mφs, as evident from triple immunofluorescence staining for stabilin-1 and Mφ markers. Stabilin-1 Mφs were often more prominent in stromal regions rather than intratumoral regions in UCB tissues (P < 0.0001). After dichotomization at the median cell density for stabilin-1 Mφs, only intratumoral stabilin-1 Mφ density was a predictor of poor OS (P < 0.001) and RFS (P = 0.026). Moreover, intratumoral stabilin-1 Mφ density was positively associated with tumor stage (P < 0.01) and histological grade (P < 0.01), and emerged as an independent prognostic factor for OS (HR 2.371; P < 0.0001), but not for RFS (HR 1.491; P = 0.061). CONCLUSIONS:Our findings indicate that intratumoral stabilin-1 Mφs could potentially be used as a pro-tumoral prognostic marker for UCB patients. 10.1007/s00345-019-02853-0
    Elevated pre-existing lymphocytic infiltrates in tumour stroma predict poor prognosis in resectable urothelial carcinoma of the bladder. Wang Bo,Xie Shujie,Bi Junming,Liu Zhuowei,Zeng Hong,Huang Hao,Xue Miaoxin,He Zhihua,Yang Meihua,Yu Hao,Huang Jian,Lin Tianxin Histopathology AIMS:Lymphocytic infiltrates are predominantly distributed in the tumour stroma, and represents the tumour-related immune response. The aim of this study was to elucidate the prognostic value of stromal lymphocytic infiltrates (SLI) in resectable urothelial carcinoma of the bladder (UCB). METHODS AND RESULTS:The prognostic significance of SLI in UCB was assessed in a discovery cohort (n = 226; 60 deaths) and in a validation cohort (n = 417; 103 deaths). SLI was categorised into intense (≥50% SLI) and non-intense (<50% SLI). A multivariable Cox model was used to analyse the associations of SLI score with overall survival (OS) and disease-free survival. Immunofluorescence staining was used to examine the composition and phenotypes of SLI. The median follow-up times were 58.1 and 64.9 months in the discovery and validation cohorts, respectively. SLI was intense in 38.1% of patients in the discovery cohort and in 20.9% of patients in the validation cohort (P < 0.001). SLI score had independent prognostic value for OS [hazard ratio (HR) 2.132; P = 0.016] and disease-specific survival (DSS) (HR 1.952; P = 0.04) in the discovery cohort, which was confirmed in the validation cohort (OS: HR 1.636; P = 0.023; DSS: HR 1.627; P = 0.029). SLI score was positively associated with histological grade, tumour stage and lymph node status in both cohorts. Moreover, in the stroma, SLI displayed a broad spectrum of inhibitory immune cells, by expressing several major immune checkpoint molecules, i.e. programmed cell death protein 1, programmed death-ligand 1, indoleamine 2,3-dioxygenase, and T-cell immunoglobulin and mucin domain 3. CONCLUSION:Intense pre-existing SLI was validated as a reliable marker of poorer prognosis for survival in UCB patients, which may add to the prognostic significance of the TNM classification. 10.1111/his.13807
    Postoperation of cervical cancer with intestine metastasis: a case report and literature review. Yu Xiuyan,Wang Zhen,Zhang Zhigang,Liu Yang,Huang Jian World journal of surgical oncology BACKGROUND:Cervical cancer can infiltrate locally and directly spread to adjacent organs including the vagina, peritoneum, urinary bladder, ureters, rectum, and paracervical tissue, but the intestine metastasis from cervical cancer is extremely rare, which can easily be misdiagnosed. CASE PRESENTATION:Here, we report a case about a 45-year-old postoperative cervical cancer patient with metastases to small intestine and sigmoid colon who presented abdominal distention and dull pain due to intestinal obstruction. The patient underwent exploratory laparotomy, and two intestinal segments including the tumors were resected. The postoperative pathological diagnosis illustrated sigmoid colon and terminal ileum metastatic squamous cell carcinoma. CONCLUSIONS:This case demonstrates that intestine metastasis must be considered in the differential diagnosis of acute abdomen in patients with cervical cancer even at an early tumor stage. 10.1186/s12957-015-0759-3
    Laparoscopic radical cystectomy with orthotopic ileal neobladder: a report of 85 cases. Huang Jian,Lin Tianxin,Xu Kewei,Huang Hai,Jiang Chun,Han Jinli,Yao Yousheng,Guo Zhenghui,Xie Wenlian,Yin Xinbao,Zhang Caixia Journal of endourology PURPOSE:The preliminary results of laparoscopic radical cystectomy in 85 patients are presented in this study. The functional and oncologic outcomes of this procedure in these patients are discussed. PATIENTS AND METHODS:Between December 2002 and May 2006, we performed 85 laparoscopic radical cystectomies with orthotopic ileal neobladder for bladder cancer in 77 men and 8 women. A 5-port transperitoneal approach was applied. The standard bilateral pelvic lymphadenectomy was performed first, then radical cystectomy was completed laparoscopically. The construction of the ileal neobladder and the anastomosis of ureter-neobladder were performed extracorporeally. The neobladder was anastomosed to the urethral stump under laparoscopy. A nerve-sparing procedure was performed for eight patients. RESULTS:The median operative time was 320 min, and the median blood loss was 280 mL. Conversion to open surgery was not necessary in any of the patients. The average time to oral intake after operation was 3.9 days. There were no perioperative mortalities. The complication rate was 14.1% (12/85), including such complications as three uretero-pouch anastomotic strictures, one vesicourethral anastomotic stricture, one pouch-vaginal fistula, one colonic pouch fistula, one ileo-pouch fistula, three ileus, one pneumonia, and one pyelonephritis. The daytime continence rate was 91.2%, and the nighttime continence rate was 82.4% at 6 months postoperatively. The neobladder capacity was about 343 mL. Surgical margins were tumor free for all patients. Of the eight patients who underwent a nerve-sparing procedure, four patients had potency for intercourse. During a follow-up period of 1 to 41 months (average 21.3 months), three patients had local recurrence, one patient had trocar site seeding, and five patients had distant metastasis, of whom four died. CONCLUSIONS:Laparoscopic radical cystectomy with extracorporeal formation of a neobladder is a feasible procedure with low morbidity and acceptable neobladder function. Long-term follow-up is needed to confirm the oncologic outcomes. 10.1089/end.2007.0298
    [Application of modified single port laparoscopic radical cystoprostatectomy and orthotopic ileal neobladder]. Huang Jian,Lin Tian-Zin,Xu Ke-Wei,Han Jin-Li,Ye Feng,Huang Hai,Jiang Chun,Zhang Cai-Xia,Yao You-Sheng,Xie Wen-Lian,Liu Hao Zhonghua yi xue za zhi OBJECTIVE:To evaluated the feasibility and therapeutic effect of laparoscopic-endoscopic single-site surgery (LESS) for radical cystoprostatectomy and orthotopic ileal neobladder. METHODS:Between November 2008 and August 2009, 8 male patients with bladder cancer underwent modified single port laparoscopic cystoprostatectomy and orthotopic ileal neobladder with a home-made multichannel port made up of two stretchable rings and a surgical glove with trocars and valves attached to its fingers. A 4 - 5 cm midline incision was made in lower abdomen and the multichannel port placed into this incision. Laparoscopic instrument was extended through the multichannel port. Another port was placed at the umbilicus site for laparoscope. The investigators performed the modified single port transperitoneal technique neobladder extracorporeally and urethro-pouch anastomosis under laparoscopy with a slipknot running suture technique. The perioperative and postoperative data were collected and analyzed prospectively. RESULTS:In all cases, no conversion into conventional laparoscopic or open surgery was necessary. The mean operative duration, including extended lymph node dissection, was 399 min (range: 355 - 455 min). Mean estimated blood loss was 154 ml (range: 90 -210 ml). The mean postoperative hospital stay was 15 d (range: 14 - 18 d). No peri-operative mortality was reported. One case had delirium 2 days postoperatively and there was no port-related complication. The pathological report confirmed surgical margins were tumor-free for all cases. The average number of removed lymph node was 20. The mean follow-up period was 6.1 months (range: 2.0 -10.0 months). All patients remained disease-free until the last follow-up. CONCLUSIONS:With a reduction of 4 ports, modified single port laparoscopic radical cystectomy with orthotopic ileal neobladder is technically feasible with a low complication rate. Our initial outcome is encouraging, but additional work and a further follow-up are warranted to critically compare the oncological outcome with open surgery.
    [Laparoscopic radical cystectomy with orthotopic ileal neobladder: report of 108 cases]. Lin Tian-Xin,Huang Jian,Xu Ke-Wei,Jiang Chun,Huang Hai,Han Jin-Li,Zhang Cai-Xia,Yao You-Sheng,Xie Wen-Lian,Guo Zheng-Hui,Yin Xin-Bao,Dong Wen Zhonghua yi xue za zhi OBJECTIVE:To analyze the effects, complication, and outcome of laparoscopic radical cystectomy. METHODS:108 patients with bladder cancer, 96 males and 12 females, aged 61 (36 - 81) underwent laparoscopic radical cystectomy with orthotopic ileal neobladder. Five-port transperitoneal approach was applied. The surgical procedure included standard laparoscopic pelvic lymphadenectomy, radical resection of bladder, extracorporeal formation of ileal pouch; extracorporeal implantation of ureters; and laparoscopic urethra-neobladder anastomosis. Erectile nerve sparing procedure was performed for 26 cases. The patients were followed up for 1 - 53 months. RESULTS:The median operation time was 330 min, and the median blood loss was 320 ml. Conversion to open surgery was not necessary in any of the patients. There was no peri-operative mortality. The complication rate was 18.5% (20/108). Surgical margins were tumor free for all cases. The day-time and night-time continence rates were 90.7% and 82.6% respectively in 6 months postoperatively. 10 of the 26 patients undergoing erectile nerve-sparing procedure had potency for intercourse. Follow-up showed 5 cases with local recurrence, 1 case with trocar site seeding and 6 cases with distant metastasis, 8 of the patients died of tumor-related disease and 3 died of diseases not related to tumor. CONCLUSION:Laparoscopic radical cystectomy with extracorporeal formation of orthotopic ileal neobladder is a feasible technique with low morbidity and acceptable neobladder function.
    Laparoscopic radical cystectomy with orthotopic ileal neobladder: report of 33 cases. Huang Jian,Xu Ke-wei,Yao You-sheng,Guo Zheng-hui,Xie Wen-lian,Jiang Chun,Han Jin-li,Li Si-yao Chinese medical journal BACKGROUND:The laparoscopic radical cystectomy (LRC) with orthotopic ileal neobladder is now applied to treat invasive bladder cancer, however, it has not been well codified and illustrated. We describe in this paper a technique step by step that we have developed in 33 patients and achieved excellent results. METHODS:The surgical procedure can be divided into eight steps: laparoscopic pelvic lymphadenectomy and mobilization of the distal ureters; exposing Denonvillier's space and the posterior aspect of prostate; exposing retropubic space and anterior surface of the bladder; dividing the lateral pedicles of the bladder and the prostate; dividing the apex of the prostate; extracorporeal formation of the ileal pouch; extracorporeal implantation of the ureters; and laparoscopic urethra-neobladder anastomosis. This operation was performed in 33 patients, 29 males and 4 females, with muscle invasive bladder cancer between December 2002 and September 2004. RESULTS:The operating time was 5.5-8.5 hours with an average of 6.5 hours; the estimated blood loss was 200-1000 ml with an average of 460 ml. The surgical margins of the bladder specimen were negative in all patients. There was no evidence of local recurrence at follow-up of 1-21 months in all the patients. However lymph node metastases were found in one case at 9 months postoperatively. Most of patients achieved urine control 1 to 3 months after surgery. The daytime continence rate was 94% (31 cases) and nighttime continence rate was 88% (29 cases). Urodynamic evaluation was performed between 3 and 6 months postoperatively for all cases. The mean value of neobladder capacity was (296 +/- 37) ml. The mean value of maximum flow rate was (18.7 +/- 7.1) ml/s. The mean residual urine volume was (32 +/- 19) ml. In all cases, excretory urography at 1 to 2 months postoperatively demonstrated slightly dilated upper urinary tracts without ureteral obstruction, which resolved at follow up. Cystography showed neobladders being similar in shapes to normal. Two small ureteral nipples with intermittently efflux of urine were observed at cystoscopy in most patients. Postoperative complications occurred in 6 of 33 patients (18%), including pouch leakage in 2 cases, pelvic infection in 1, partial small bowel obstruction in 2 and neobladder-vaginal fistula in 1. CONCLUSIONS:The LRC with orthotopic ileal neobladder is a feasible option for bladder cancer when radical cystectomy is indicated. The extracorporeal formation of the ileal pouch and ureteral implantation through a small lower midline incision can simplify the complexity of the procedures, shorten the duration of surgery and reduce the medical expenses.
    Systematic review and meta-analysis of comparative studies reporting early outcomes after robot-assisted radical cystectomy versus open radical cystectomy. Li Kaiwen,Lin Tianxin,Fan Xinxiang,Xu Kewei,Bi Liangkuan,Duan Yu,Zhou Yu,Yu Min,Li Jielin,Huang Jian Cancer treatment reviews BACKGROUND:Robot-assisted radical cystectomy (RARC) is increasingly being used in the management of bladder cancer. Studies comparing RARC and open radical cystectomy (ORC) have reported conflicting results. We conducted a systematic review and meta-analysis of the literature on the efficacy and advantages of RARC compared with ORC. METHODS:An electronic database search of PubMed, Scopus, and the Cochrane Library was performed up to July 8, 2012. This systematic review and meta-analysis was performed based on all randomized controlled trials (RCTs) and observational comparative studies assessing the two techniques. RESULTS:One RCT, eight studies with prospectively collected data, and four retrospective studies were identified, including 962 cases. Although RARC was associated with longer operative time (p<0.001), patients in this group might benefit from less overall perioperative complications (p=0.04), more lymph node yield (p=0.009), less estimated blood loss (p<0.001), a lower need for perioperative transfusion (p<0.001), and shorter length of hospital stay (p<0.001). Positive surgical margins did not differ significantly between techniques. Sensitivity analysis with prospective studies showed similar results to the original analysis, but no significant difference of lymph node yield and length of stay between two techniques. CONCLUSIONS:RARC is a mini-invasive alternative to ORC with less overall perioperative complications, more lymph node yields, less estimated blood loss, less need for a perioperative transfusion, and shorter length of stay. 10.1016/j.ctrv.2012.11.007
    Improved detection of nonmuscle invasive urothelial carcinoma of the bladder using pirarubicin endoscopy: a prospective, single-center preliminary study. Han Jinli,Lin Tianxin,Xu Kewei,Jiang Chun,Huang Hai,Yin Xinbao,Xie Wenlian,Yao Yousheng,Zhang Caixia,Huang Jian Journal of endourology BACKGROUND AND PURPOSE:Fluorescence cystoscopy (FC) with intravesical instillation of a photosensitizing agent has emerged as an adjunctive and safe diagnostic tool with high sensitivity and reasonable specificity; however, it has not been widely accepted, because it is time-consuming and expensive. The aim of the present study was to determine whether the use of the fluorescent dye pirarubicin [(2"R)-4'-O-tetrahydropyranyl doxorubicin] (THP) in endoscopy can improve detection of nonmuscle invasive urothelial carcinoma of the bladder. PATIENTS AND METHODS:Forty-eight patients with known or suspected bladder urothelial carcinoma were enrolled in this prospective study between January 2008 and April 2009. The Storz D-light system was used to detect fluorescence 15 minutes after intravesical instillation with 30 mg THP. Endoscopic findings, histopathologic evaluation of biopsy lesions, and adverse effects of THP were recorded. RESULTS:After THP uptake, the lesions appear bright orange under white light, and produce bright red fluorescence under blue light. Among 238 biopsies evaluated (84 malignant, 20 dysplasia, and 134 benign), sensitivity of overall tumors, carcinoma in situ (CIS), and dysplasia detection using FC was 96% (81/84), 100% (6/6), and 90% (18/20), respectively. The specificity of FC was 74.7% (115/154), and its false-positive rate was 32.5% (39/120). No significant systemic side effects or allergic reactions were observed other than a few cases of mild cystitis. CONCLUSION:THP endoscopy may improve the detection of nonmuscle invasive urothelial carcinoma of the bladder, especially CIS and flat lesions. Results indicate that THP is a promising fluorescent dye for diagnosis and follow-up of nonmuscle invasive bladder carcinoma. Moreover, it is inexpensive, easily available, simple to administer, and is associated with few side effects. 10.1089/end.2009.0680
    Hybrid laparoscopic endoscopic single-site surgery for radical cystoprostatectomy and orthotopic ileal neobladder: an initial experience of 12 cases. Lin Tianxin,Huang Jian,Han Jinli,Xu Kewei,Huang Hai,Jiang Chun,Liu Hao,Zhang Caixia,Yao Yousheng,Xie Wenlian,Shah Arvind Kumar,Huang Li Journal of endourology BACKGROUND AND PURPOSE:Laparoscopic endoscopic single-site surgery (LESS) has recently emerged as an attempt to enhance cosmetic benefits and reduce morbidity; however, LESS for radical cystectomy is still not well established. Here we describe the technique of hybrid LESS for radical cystoprostatectomy and orthotopic ileal neobladder (RC-OIN), and evaluate its feasibility and safety. PATIENTS AND METHODS:Between November 2008 and October 2009, 12 men with bladder cancer underwent hybrid LESS for RC-OIN. A homemade multichannel port, made from two stretchable rings and a surgical glove with trocars and valves attached to its fingers, was placed into a 4- to 5-cm midline incision in the lower abdomen and was used for laparoscopic instruments. Another subumbilical port was placed for the laparoscope. Extended bilateral pelvic lymphadenectomy was performed by the lateral view; radical cystoprostatectomy was completed laparoscopically; construction of the ileal neobladder was performed extracorporeally; and the neobladder was anastomosed to the urethral stump laparoscopically, with a slipknot running suture technique. Perioperative, functional, oncologic data and complications were collected and analyzed. RESULTS:All operations were performed successfully without conversion to conventional laparoscopic radical cystectomy or open surgery. There was no perioperative mortality or port-related complications. The median operative time was 383 minutes. Median blood loss was 150 mL. A median of 25 lymph nodes were removed. Surgical margins were tumor free in all cases. CONCLUSIONS:Hybrid LESS for RC-OIN is technically feasible with effects similar to those of conventional laparoscopic procedures. Further instrument and technique improvement are necessary to shorten operative time and reduce intraoperative difficulties. 10.1089/end.2010.0332
    [Expression of extracellular matrix metalloproteinase inducer in human bladder transitional cell carcinoma]. Han Jin-Li,Xie Wen-Lian,Huang Jian,Yao You-Sheng Ai zheng = Aizheng = Chinese journal of cancer BACKGROUND & OBJECTIVE:Matrix metalloproteinases(MMPs) play critical roles in the process of tumorigenesis, tumor invasion and metastasis. Extracellular matrix metalloproteinase inducer (EMMPRIN) derived from cancer cell can induce stromal fibroblasts to synthesize MMPs, which advances the invasion and metastasis of cancer. This study was designed to investigate the roles of EMMPRIN in the tumorigenesis, invasion and metastasis of bladder carcinoma by detecting the expression of EMMPRIN in human normal and carcinomatous bladder tissues. METHODS:The expression of EMMPRIN was examined in 45 bladder carcinoma tissues from 45 patients and normal bladder mucosa from 9 persons by immunohistochemistry SP method. The relationship between EMMPRIN expression and clinicopathologic parameters was analyzed. RESULTS:EMMPRIN protein was localized at membrane and cytoplasm of carcinomatous epithelial cell, but was not expressed in normal bladder epithelial or tumor stromal cell. The overall positive rate of EMMPRIN in 45 cases of bladder carcinoma was 73%. The positive rates of EMMPRIN in grade II, grade III and recurrent carcinomas were 84%, 85%, and 100%, respectively, significantly higher than those in grade I and non-recurrent carcinomas (14% and 56%, respectively) (P< 0.05). The intensive positive rate of EMMPRIN in lymph node metastasis group (86%) was significantly higher than that in no lymph node metastasis group (24%) (P< 0.05). CONCLUSION:EMMPRIN was overexpressed in human bladder transitional cell carcinoma, and related to the malignant degree and recurrence. It could be a useful indicator for the assessment of potent invasion and metastasis of bladder carcinoma.
    The utility of fluorescence in situ hybridization for diagnosis and surveillance of bladder urothelial carcinoma. Huang Jian Wen,Mu Jia Gui,Li Yun Wei,Gan Xiu Guo,Song Lu Jie,Gu Bao Jun,Fu Qiang,Xu Yue Min,An Rui Hua Urology journal PURPOSE:To evaluate the clinical value of fluorescence in situ hybridization (FISH) for diagnosis and surveillance of bladder urothelial carcinoma (BUC). MATERIALS AND METHODS:Between November 2010 and December 2013, patients suspected of having BUC were examined using urine cytology and FISH assay. Based on histopathological examination results, FISH results were com­pared with urine cytology. In addition, patients with a history of non-muscle invasive BUC were also examined using urine cytology and FISH assay at the first time of visit and then monitored with cystoscopy during follow-up period. RESULTS:A total of 162 patients included in this study and 12 patients were excluded due to uninformative FISH assays. The remaining 150 patients consisted of 108 patients suspected for BUC and 42 patients with a history of non-muscle invasive BUC. The sensitivities of FISH analysis and urine cytology were 72.8% and 27.2%, respectively, and the difference was statistically significant (P <.05). Difference between specificity of urine cytology (100%) and FISH assay (85%) was not statistically significant (P >.05). At the first visit, of 42 patients, one patient had positive cystoscopy, and FISH assay was positive in 26 of 41 patients with negative cystoscopy. During the follow-up period (mean, 29.5 months), 18 of 26 patients developed recurrence, and recurrence occurred in only one of 15 patients with negative FISH analysis. CONCLUSION:Our results suggest that FISH analysis can be used as a non-invasive diagnostic tool for patients suspect­ed of having new BUC. In addition, FISH analysis may provide important prognostic information to better define the individual risk for BUC recurrence.& nbsp;
    Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells. Wang Xiaolin,Wu Guang,Cao Guangxin,Yang Lei,Xu Haifei,Huang Jian,Hou Jianquan Molecular medicine reports Zoledronic acid (ZA) is the current standard of care for the therapy of patients with bone metastasis or osteoporosis. ZA inhibits the prenylation of small guanosine‑5'-triphosphate (GTP)‑binding proteins, such as Ras, and thus inhibit Ras signaling. The present study demonstrated that ZA inhibited cell proliferation and the pentose phosphate pathway (PPP) in bladder cancer cells. In addition, the expression of glucose‑6‑phosphate dehydrogenase (G6PD, the rate‑limiting enzyme of the PPP) was found to be inhibited by ZA. Furthermore, the stability of TAp73, which activates the expression G6PD was decreased in zoledronic acid treated cells. Decreased levels of Ras‑GTP and phosphorylated‑extracellular signal-regulated kinase 1/2 were also observed following treatment with ZA. This may be due to the fact that activated Ras was reported to stabilize TAp73 inducing its accumulation. The inhibition of Ras activity by PT inhibitor II also significantly reduced the levels of TAp73 and G6PD and the PPP flux. Moreover, knockdown of TAp73, attenuated the PPP flux and eliminated the affection of ZA on the PPP flux. In conclusion, it was proposed that ZA can inhibit stability of TAp73 and attenuate the PPP via blocking Ras signaling in bladder cancer cells. 10.3892/mmr.2015.3995
    Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. Chen Changhao,Luo Yuming,He Wang,Zhao Yue,Kong Yao,Liu Hongwei,Zhong Guangzheng,Li Yuting,Li Jun,Huang Jian,Chen Rufu,Lin Tianxin The Journal of clinical investigation Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C-independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell-secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell-secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C-independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa. 10.1172/JCI130892
    Diagnostic performance of image technique based transurethral resection for non-muscle invasive bladder cancer: systematic review and diagnostic meta-analysis. Chen Changhao,Huang Hao,Zhao Yue,Liu Hao,Sylvester Richard,Lin Tianxin,Huang Jian BMJ open OBJECTIVE:To explore the diagnostic performance of image technique based transurethral resection for bladder cancer, with white light-guided cystoscopy (WLC) as the reference standard. DESIGN:Systematic review and meta-analysis. DATA SOURCES:PubMed/MEDLINE, Web of Science, the Cochrane Library, Central Register of Controlled Trials and Embase from inception to 31 March 2018. METHODS:Included studies reported the diagnostic performance of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA), PDD with hexaminolevulinic acid (HAL) or narrow band imaging (NBI), with WLC as the reference standard at the patient or lesion level. The studies' risk of bias (RoB) was assessed using Quality Assessment of Diagnostic Studies-2. Data were pooled using a random effect diagnostic meta-analysis, and subgroup analyses were performed. RESULTS:Twenty-six studies comprising a total of 3979 patients were included in this diagnostic meta-analysis. Pooled sensitivity (SSY), specificity (SPY), diagnostic OR (DOR) and area under the receiver operating characteristic curve (AUROC) values were calculated per group for NBI, HAL and 5-ALA at the lesion or patient level. NBI showed significant diagnostic superiority compared with WLC at the lesion level (SSY 0.94, 95% CI 0.82 to 0.98; SPY 0.79, 95% CI 0.73 to 0.85; DOR 40.09, 95% CI 20.08 to 80.01; AUROC 0.88, 95% CI 0.85 to 0.91). NBI presented the highest DOR (358.71, 95% CI 44.50 to 2891.71) in the patient level. Subgroup analyses were performed on studies with low to moderate RoB and at least 100 patients at the lesion level. These results were consistent with those of the overall analysis. CONCLUSIONS:Pooled data indicated that image technique based transurethral resection (NBI, HAL and 5-ALA) showed diagnostic superiority compared with WLC. Moreover, NBI is potentially the most promising diagnostic intervention, showing the best diagnostic performance outcomes. Further prognostic outcomes of novel imaging technologies compared with those WLC should be explored in addition to current diagnostic performance analysis. 10.1136/bmjopen-2018-028173
    Circular RNA circPICALM sponges miR-1265 to inhibit bladder cancer metastasis and influence FAK phosphorylation. Yan Dong,Dong Wei,He Qingqing,Yang Meihua,Huang Lifang,Kong Jianqiu,Qin Haide,Lin Tianxin,Huang Jian EBioMedicine BACKGROUND:Metastasis is a major obstacle in the treatment of bladder cancer (BC). Circular RNAs exert various functions in the aggressive biological behaviour of cancers. In this study, we aimed to elucidate how circPICALM influences BC metastasis. METHODS:The expression of circPICALM was analysed by real-time PCR. The tumourigenic properties of BC cells were evaluated using in vitro migration, invasion, and wound healing assays and an in vivo footpad model. The interaction between circPICALM and miR-1265 was confirmed by pull-down and dual-luciferase reporter assays and biotin-labelled miRNA capture. The interaction of STEAP4 and focal adhesion kinase (FAK) was confirmed by co-immunoprecipitation. FINDINGS:CircPICALM was downregulated in BC tissues, and low circPICALM expression was related to advanced T stage, high grade, lymph node positivity and poor overall survival. Overexpression of circPICALM inhibited the metastasis of BC cells, and DHX9 negatively regulated circPICALM levels. CircPICALM colocalized with miR-1265 and acted as a sponge for this miRNA, and the pro-invasion effect of miR-1265 was abolished by circPICALM overexpression. STEAP4, a target of miR-1265, suppressed metastasis; it bound to FAK to prevent autophosphorylation at Y397 and influenced EMT in BC cells. INTERPRETATION:CircPICALM can inhibit BC metastasis and bind to miR-1265 to block its pro-invasion activity. STEAP4 is a target of miR-1265 and is related to FAK phosphorylation and EMT. FUND: This research was supported by National Natural Science Foundation of China, No.81772728, National Natural Science Foundation of China, No.81772719, National Natural Science Foundation of China No.81572514. 10.1016/j.ebiom.2019.08.074
    Diagnostic accuracy of photodynamic diagnosis with 5-aminolevulinic acid, hexaminolevulinate and narrow band imaging for non-muscle invasive bladder cancer. Chen Changhao,Huang Hao,Zhao Yue,Liu Hao,Luo Yuming,Sylvester Richard J,Li Jia Ping,Lam Thomas B,Lin Tianxin,Huang Jian Journal of Cancer To assess the diagnostic test accuracy (DTA) of photodynamic diagnosis with 5-aminolaevulinic acid (5-ALA), hexylaminolevulinate (HAL) and narrow band imaging (NBI) for non-muscle-invasive bladder cancer (NMIBC), with white light-guided cystoscopy (WLC) as reference standard. A systematic review and narrative synthesis was performed in accordance with PRISMA. Major electronic databases were searched until 20 May 2019. All studies assessing the DTA of 5-ALA, HAL and NBI compared with WLC at patient and lesion-level were included. Relevant sensitivity analyses and risk of bias (RoB) assessment were undertaken. 26 studies recruiting 3979 patients were eligible for inclusion. For patient-level analysis, NBI appeared to be the best (median sensitivity (SSY) 100%, median specificity (SPY) 68.45%, median positive predictive value (PPV) 90.75%, median negative predictive value (NPV) 100% and median false positive rate (FPR) 31.55%), showing better DTA outcomes than either HAL or 5-ALA. For lesion-level analysis, median SSY across NBI, HAL and 5-ALA were 93.08% (IQR 87.04-98.81%), 93.16% (IQR 91.48-97.04%) and 94.42% (IQR 82.37-95.73%) respectively. As for FPR, median values for NBI, HAL and 5-ALA were 20.40% (IQR 13.68-27.36%), 17.43% (IQR 12.79-22.40%) and 28.12% (IQR 22.08-42.39%), respectively. Sensitivity analyses based on studies with low to moderate RoB and studies with n>100 patients show similar findings. NBI appears to outperform 5-ALA and HAL in terms of diagnostic accuracy. All three modalities present high FPR, hence indicating the ability to detect additional cases and lesions beyond WLC. 10.7150/jca.34527
    CircPTPRA acts as a tumor suppressor in bladder cancer by sponging miR-636 and upregulating KLF9. He Qingqing,Huang Lifang,Yan Dong,Bi Junming,Yang Meihua,Huang Jian,Lin Tianxin Aging Growing evidence suggests that circular RNAs (circRNAs) play pivotal roles in cancer progression. In this study, bioinformatic analysis identified a dysregulated circRNA termed circPTPRA in bladder cancer (BC). By using qRT-PCR analysis, we verified that circPTPRA is down-regulated in clinical BC specimens compared with the matched non-tumor samples, while correlation analyses showed that low circPTPRA expression is associated with poor prognosis, advanced tumor stage and larger tumor size. Based on these findings, we conducted functional assays and revealed that circPTPRA inhibits BC cell proliferation in vitro and tumor growth in vivo. In addition, RNA pull-down, miRNA capture, FISH, and luciferase reporter assays demonstrated that circPTPRA can directly sponge miR-636. Cell transfection experiments showed that miR-636 promotes the proliferation of BC cells by decreasing the expression of Krüppel Like Factor 9 (KLF9) upon binding to the 3'UTR of its mRNA.Further analysis confirmed that circPTPRA competitively sponges miR-636 to upregulate the KLF9 expression, leading to decreased proliferation of BC cells. Our investigation indicates that circPTPRA acts as a tumor suppressor in BC, and suggests that this circRNA may be a novel prognostic biomarker and therapeutic target in BC. 10.18632/aging.102530
    Gene expression profiling of WDR5 regulated genes in bladder cancer. Chen Xu,Gu Peng,Li Kuiqing,Xie Weibin,Chen Changhao,Lin Tianxin,Huang Jian Genomics data WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription (Wysocka et al., 2005 [1]; Sandstrom et al., 2014[2]; Ang et al., 2011[3]). Recently, our study found that WDR5 was upregulated in bladder cancer tissues, promoted bladder cancer cell proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro, and tumor growth in vivo (Chen et al., 2015). To gain a molecular understanding of the role of WDR5 in promoting bladder cancer, we performed a genome-wide analysis on WDR5 knockdown by microarray gene expression profiling. Here we provide detailed experimental methods and analysis for the microarray data, which have been deposited into Gene Expression Omnibus (GEO): GSE59132. 10.1016/j.gdata.2015.05.003
    Circular RNA circ-ZKSCAN1 inhibits bladder cancer progression through miR-1178-3p/p21 axis and acts as a prognostic factor of recurrence. Bi Junming,Liu Hongwei,Dong Wei,Xie Weibin,He Qingqing,Cai Zijian,Huang Jian,Lin Tianxin Molecular cancer BACKGROUND:Circular RNAs (circRNAs) represent a subclass of regulatory RNAs that have been shown to have significant regulatory roles in cancer progression. However, the biological functions of circRNAs in bladder cancer (BCa) are largely unknown. METHODS:Cell invasion models were established, and invasion-related circRNAs were detected by qPCR. Using above method, circ-ZKSCAN1 was picked out for further study. Circ-ZKSCAN1 expression and survival analyses were performed through qPCR. The survival curves were generated by the Kaplan-Meier method, and the log-rank test was used to assess the significance. Cell proliferation, migration and invasion were examined to investigate the function of circ-ZKSCAN1. Tumorigenesis in nude mice was assessed to determine the effect of circ-ZKSCAN1 in bladder cancer. Biotin-coupled probe pull-down assays, FISH and luciferase reporter assays were conducted to confirm the relationship between circ-ZKSCAN1 and microRNA. RNA-seq revealed different molecular changes in downstream genes. RESULTS:Here, we found that circ-ZKSCAN1 was downregulated in BCa tissues and cell lines. Circ-ZKSCAN1 levels were associated with survival, tumor grade, pathological T stage and tumor recurrence. Overexpressed circ-ZKSCAN1 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo. Mechanistically, we demonstrated that circ-ZKSCAN1 upregulated p21 expression by sponging miR-1178-3p, which suppressed the aggressive biological behaviors in bladder cancer. CONCLUSIONS:These results reveal that Circ-ZKSCAN1 acts as a tumor suppressor via a novel circ-ZKSCAN1/miR-1178-3p/p21 axis, which have the important role in the proliferation, migration and invasion ablitities of BCa cells and provide a novel perspective on circRNAs in BCa progression. 10.1186/s12943-019-1060-9
    Long Noncoding RNA Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2. Chen Xu,Xie Ruihui,Gu Peng,Huang Ming,Han Jinli,Dong Wen,Xie Weibin,Wang Bo,He Wang,Zhong Guangzheng,Chen Ziyue,Huang Jian,Lin Tianxin Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells () has been identified and explored in BCSCs. EXPERIMENTAL DESIGN:Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of are analyzed in three independent large-scale cohorts. The functional role and mechanism of are further investigated by gain- and loss-of-function assays and . RESULTS: is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both and . Mechanistically, directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. CONCLUSIONS:As a novel regulator, plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The -hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer. 10.1158/1078-0432.CCR-18-1656
    Laparoscopic radical cystectomy with orthotopic ileal neobladder for bladder cancer: oncologic results of 171 cases with a median 3-year follow-up. Huang Jian,Lin Tianxin,Liu Hao,Xu Kewei,Zhang Caixia,Jiang Chun,Huang Hai,Yao Yousheng,Guo Zhenghui,Xie Wenlian European urology BACKGROUND:Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard treatment for muscle-invasive and high-risk non-muscle-invasive bladder cancer (BCa). Large series with long-term oncologic data after laparoscopic RC (LRC) are rare. OBJECTIVE:To report oncologic outcomes of LRC for 171 cases with a median 3-yr follow-up. DESIGN, SETTING, AND PARTICIPANTS:From December 2002 to June 2009, 171 consecutive patients with BCa who underwent LRC with orthotopic ileal neobladder (OIN) at our institution were enrolled in this retrospective study. INTERVENTION:All patients underwent LRC OIN. Adjuvant chemotherapy was administered to patients with non-organ-confined disease or positive lymph nodes. MEASUREMENTS:The demographic, perioperative, complication, pathologic, and survival data were collected and analysed. RESULTS AND LIMITATIONS:Most tumours were transitional cell carcinoma (TCC; 160, 93.6%). Tumours were organ confined in 113 patients (pT1-T2; 66.1%) and non-organ confined in 58 patients (pT3-T4a; 33.9%). There was involvement of the lymph nodes in 38 patients (22.2%). Surgical margins were all tumour free. The mean number of removed lymph nodes was 16 (5-46). Follow-up ranged from 3 to 83 mo, and 54 (31.6%) patients completed 5-yr follow-up. Two patients (1.2%) had local recurrence and distant metastasis, 9 patients (5.3%) had local recurrence alone, and 23 patients (13.5%) had distant metastasis. One patient (0.6%) had port-site seeding. One hundred twenty-four patients (72.5%) were alive with no evidence of recurrence; 28 patients (16.4%) died, 20 from metastasis and 8 from tumour-unrelated causes. The estimated 5-yr overall survival, cancer-specific survival, and recurrence-free survival rates were 73.7%, 81.3%, and 72.6%, respectively. The relatively low percentage of patients reaching 5-yr follow-up is a limitation of this retrospective study. CONCLUSIONS:Surgical technique of LRC with OIN can achieve the established oncologic criteria of open surgery, and our oncologic outcome is encouraging. Long-term follow-up is needed for further confirmation. 10.1016/j.eururo.2010.05.046
    High CD204+ tumor-infiltrating macrophage density predicts a poor prognosis in patients with urothelial cell carcinoma of the bladder. Wang Bo,Liu Hao,Dong Xiaoliang,Wu Shaoxu,Zeng Hong,Liu Zhuowei,Wan Di,Dong Wen,He Wang,Chen Xu,Zheng Limin,Huang Jian,Lin Tianxin Oncotarget Macrophages (Mφs) are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study attempted to investigate the prognostic values of various tumor-infiltrating Mφ phenotypes in patients with urothelial cell carcinoma of the bladder (UCB), with a focus on Mφ tissue microlocalization. Mφs were assessed by immunohistochemistry in tissues from 302 UCB patients using CD68 as a pan-Mφ marker, and CD204 and CD169 as robust pro- and anti-tumoral Mφ phenotype markers, respectively. Our data showed that these Mφ phenotypes were predominately distributed in stromal (ST) rather than in intratumoral (INT) regions (all P < 0.0001). Surprisingly, CD204 and CD169 can be co-expressed by the same CD68+ Mφs. Kaplan-Meier analysis revealed that all INT- and ST-infiltrating CD204+ or CD169+ Mφ densities were inversely associated with overall survival (all P < 0.01). By multivariate analysis, ST-infiltrating CD204+ Mφ density emerged as an independent prognostic factor for overall survival (HR, 1.981; P = 0.022). Moreover, the density of ST-infiltrating CD204+ Mφs was positively associated with the tumor size (P = 0.001), tumor stage (P < 0.0001), nodal metastasis (P < 0.0001), and histological grade (P < 0.0001). Our findings suggest that CD204+ Mφs might play detrimental protumoral roles and represent the predominant Mφ phenotype in human bladder cancer. 10.18632/oncotarget.3887
    CD103+ Tumor Infiltrating Lymphocytes Predict a Favorable Prognosis in Urothelial Cell Carcinoma of the Bladder. Wang Bo,Wu Shaoxu,Zeng Hong,Liu Zhuowei,Dong Wen,He Wang,Chen Xu,Dong Xiaoliang,Zheng Limin,Lin Tianxin,Huang Jian The Journal of urology PURPOSE:CD8(+) TILs at different tumor sites have diverse clinical attributes, which might result from distinct tumor microenvironments that promote differentiation into distinct subsets. However, only a few markers have been identified that can define CD8(+) T-cell subsets. CD103 is a marker of tissue resident memory CD8(+) T cells. In this retrospective study we investigated the cellular source and clinical significance of CD103 expression in urothelial cell carcinoma of bladder tissues in situ. MATERIALS AND METHODS:Immunohistochemistry and immunofluorescence were used to identify the cellular source of CD103 in bladder urothelial cell carcinoma tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall and recurrence-free survival in 302 patients with bladder urothelial cell carcinoma. RESULTS:CD8(+) T cells but not natural killer cells accounted for most CD103 expressing cells in bladder urothelial cell carcinoma tissues. Notably CD103(+) cells were predominantly located in intratumor regions rather than in associated stroma (p < 0.0001). The density of intratumor CD103(+) TILs was inversely associated with tumor size (p < 0.0001) and could represent a favorable prognostic predictor of overall and recurrence-free survival (p = 0.002 and 0.011, respectively). Moreover, intratumor CD103(+) TILs were positively associated with the expression of cognate ligand E-cadherin in intratumor regions of bladder urothelial cell carcinoma tissues (p = 0.008). CONCLUSIONS:Our findings suggest that CD8(+) T cells might have a significant role in tumor immunity by expressing CD103 in intratumor regions of bladder urothelial cell carcinoma tissues. Intratumor CD103(+) TILs could potentially serve as a prognostic marker in patients with bladder urothelial cell carcinoma. 10.1016/j.juro.2015.02.2941
    Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis. Dong Wei,Bi Junming,Liu Hongwei,Yan Dong,He Qingqing,Zhou Qianghua,Wang Qiong,Xie Ruihui,Su Yinjie,Yang Meihua,Lin Tianxin,Huang Jian Molecular cancer BACKGROUND:Circular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. However, the aberrant expression profile and dysfunction of circRNAs in human bladder cancer remain to be investigated. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer. METHODS:circACVR2A (hsa_circ_0001073) was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. The role of circACVR2A in bladder cancer was assessed both in vitro and in vivo. Biotin-coupled probe pull down assay, biotin-coupled microRNA capture, dual-luciferase reporter assay, and fluorescence in situ hybridization were conducted to evaluate the interaction between circACVR2A and microRNAs. RESULTS:The expression of circACVR2A was lower in bladder cancer tissues and cell lines. The down-regulation of circACVR2A was positively correlated with aggressive clinicopathological characteristics, and circACVR2A served as an independent risk factor for overall survival in bladder cancer patients after cystectomy. Our in vivo and in vitro data indicated that circACVR2A suppressed the proliferation, migration and invasion of bladder cancer cells. Mechanistically, we found that circACVR2A could directly interact with miR-626 and act as a miRNA sponge to regulate EYA4 expression. CONCLUSIONS:circACVR2A functions as a tumor suppressor to inhibit bladder cancer cell proliferation and metastasis through miR-626/EYA4 axis, suggesting that circACVR2A is a potential prognostic biomarker and therapeutic target for bladder cancer. 10.1186/s12943-019-1025-z
    Programmed death ligand-1 is associated with tumor infiltrating lymphocytes and poorer survival in urothelial cell carcinoma of the bladder. Wang Bo,Pan Wenwei,Yang Meihua,Yang Wenjuan,He Wang,Chen Xu,Bi Junming,Jiang Ning,Huang Jian,Lin Tianxin Cancer science Drugs blocking programmed death ligand-1 (PD-L1) have shown unprecedented activity in metastatic and unresectable bladder cancer. The purpose of the present study was to investigate the expression, clinical significance and association of PD-L1 with tumor-infiltrating lymphocytes (TIL) in resectable urothelial cell carcinoma of the bladder (UCB). In this retrospective study, 248 UCB patients who received radical cystectomy or transurethral resection were examined. Immunohistochemistry was used to evaluate PD-L1 expression and stromal CD8 TIL, Th1 orientation T cell (T-bet ) and PD-1 TIL densities within the intratumoral regions and associated stromal regions. Of the 248 specimens, 23% showed PD-L1 expression in tumor cells and 55% in tumor-infiltrating immune cells. CD8 TIL, T-bet TIL and PD-1 TIL were distributed throughout the tumor tissues and were more frequently distributed in stromal regions than in intratumoral regions. PD-L1 tumor cells and PD-L1 immune cells were positively associated with aggressive clinical features (all P < .05). Both PD-L1 tumor cells and PD-L1 immune cells were associated with poorer recurrence-free and overall survival (all P < .05). Multivariate analysis showed that PD-L1 immune cells were an independent prognostic factor for overall (P = .001) and recurrence-free survival (P = .024). Notably, high stromal CD8 TIL and PD-1 TIL density were associated with poorer overall survival (P = .031 and P = .001, respectively). In the stroma, CD8 TIL density has strong positive association with PD-L1 immune cells and PD-1 TIL density (all P < .0001). These results suggested that an exhausted immune state occurred in the tumor stroma in UCB. Further clinical development of immune-checkpoint inhibitors may be effective for resectable patients with UCB. 10.1111/cas.13887
    MicroRNA-143 as a tumor suppressor for bladder cancer. Lin Tianxin,Dong Wen,Huang Jian,Pan Qiuhui,Fan Xinlan,Zhang Caixia,Huang Li The Journal of urology PURPOSE:We investigated the expression and involvement of miRNA in bladder cancer. MATERIALS AND METHODS:An miRNA array was used to examine the differential expression of miRNA in tumor tissues and normal matched controls. The expression of miRNA-143 was confirmed by Northern blot and real-time polymerase chain reaction. The functional role of miRNA-143 in bladder cancer was studied by examining cell proliferation and oncogene expression after miRNA-143 transfection into 2 transitional carcinoma cell lines. RESULTS:miRNA profiling of human bladder cancer and matched normal urothelial epithelium controls revealed that 37 miRNAs were up-regulated and 38 were down-regulated in cancer tissues, of which the expression of miRNA-143 was 13.7 times lower in tumor than in the matched control. Consistent with microarray data, Northern blot analysis and real-time polymerase chain reaction confirmed that miRNA-143 expression was significantly down-regulated in bladder tumor tissues compared with normal adjacent tissues. The expression of miRNA-143 was not detected in the 2 human bladder cancer cell lines EJ and T24. Interestingly miRNA-143 transfection into EJ and T24 cells significantly inhibited cell proliferation. RAS protein expression in cancer tissues was much higher than in adjacent controls. Consistently RAS protein expression was also significantly decreased in miRNA-143 transfected cells compared with nonspecific miRNA transfected cells. CONCLUSIONS:miRNAs are differentially expressed in bladder cancer tissues. miRNA-143 may function as a tumor suppressor in bladder transitional cell carcinoma. 10.1016/j.juro.2008.10.149
    13-Methyltetradecanoic acid induces mitochondrial-mediated apoptosis in human bladder cancer cells. Lin Tianxin,Yin XinBao,Cai Qingqing,Fan Xinlan,Xu Kewei,Huang Li,Luo Junhua,Zheng Jianping,Huang Jian Urologic oncology OBJECTIVE:13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, is known to induce apoptosis in many types of human cancer cells. This study was designed to investigate the molecular mechanisms involved in 13-MTD-induced apoptosis in human bladder cancer cells. METHODS AND MATERIALS:MTT assay was used to investigate the potential effects of 13-MTD on the growth and viability of human bladder cancer cells. To find out whether anti-proliferation and cell death were associated with apoptosis, we used flow cytometry to quantify the extent of apoptosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to measures DNA degradation of apoptotic cells. The proteins involved in the 13-MTD induced apoptosis were examined using Western blot. RESULTS:We show that 13-MTD inhibits cellular proliferation and viability in human bladder cancer cells, which has been attributed to apoptosis. 13-MTD down-regulates Bcl-2 and up-regulates Bax. This promotes mitochondrial dysfunction, leading to the release of cytochrome c from the mitochondria to the cytoplasm, as well as the proteolytic activation of caspases. Moreover, 13-MTD down-regulates AKT phosphorylation and activates phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Up-regulating AKT phosphorylation and down-regulating JNK and P38 phosphorylation could attenuate the13-MTD-induced apoptosis. CONCLUSION:Taken together, these data indicate that 13-MTD induces mitochondrial-mediated apoptosis through regulation of the AKT and MAPK pathways, suggesting 13-MTD is a potential candidate for treatment of human bladder cancer. 10.1016/j.urolonc.2010.04.011
    Diagnosis of narrow-band imaging in non-muscle-invasive bladder cancer: a systematic review and meta-analysis. Li Kaiwen,Lin Tianxin,Fan Xinxiang,Duan Yu,Huang Jian International journal of urology : official journal of the Japanese Urological Association OBJECTIVES:The objective was to evaluate the diagnostic accuracy of cystoscopy assisted by narrow-band imaging compared with white-light imaging for non-muscle-invasive bladder cancer. METHODS:An electronic database search of PubMed, Embase, the Cochrane Library, Ovid and Web of Science was carried out for all articles comparing narrow-band imaging with white-light imaging cystoscopy in the detection of non-muscle-invasive bladder cancer. The review process followed the guidelines of the Cochrane Collaboration. RESULTS:Seven studies with prospectively collected data including a total of 1040 patients were identified, and 611 patients with 1476 tumors were detected by biopsy. In the patient- and tumor-level analysis, an additional 17% of patients (95% confidence interval, 10-25%) and an additional 24% of tumors (95% confidence interval, 17-31%) were detected by narrow-band imaging, respectively. In the patient- and tumor-level analysis, significantly higher detection rates using narrow-band imaging (rate difference 11%; 95% confidence interval 5-17%; P < 0.001; and rate difference 19%; 95% confidence interval 12-26%; P < 0.001, respectively) rather than white-light imaging were found. On the tumor level, an additional 28% of carcinoma in situ was detected (95% confidence interval 14-45%) by narrow-band imaging, and a significantly higher detection rate (rate difference 11%; 95% confidence interval 1-21%; P = 0.03) was found. The false-positive detection rate of tumor level did not differ significantly between the two techniques. CONCLUSIONS:Cystoscopy assisted by narrow-band imaging detects more patients and tumors of non-muscle-invasive bladder cancer than white-light imaging, and it might be an additional or alternative diagnostic technique for non-muscle-invasive bladder cancer. 10.1111/j.1442-2042.2012.03211.x
    Efficacy of immediate instillation combined with regular instillations of pirarubicin for Ta and T1 transitional cell bladder cancer after transurethral resection: a prospective, randomized, multicenter study. Li Ning-chen,Ye Zhang-qun,Na Yan-qun, Chinese medical journal BACKGROUND:Immediate intravesical instillation of chemotherapeutic agents after transurethral resection (TUR) of nonmuscle invasive transitional cell bladder cancer has recently been suggested and has been proven to decrease the tumor recurrence rate significantly. This study is to evaluate the efficacy and safety of immediate intravesical instillation combined with regular instillations of Pirarubicin (THP(®)) as prophylaxis compared to regular instillations only after TUR operation. METHODS:This was a prospective, randomized, multi-center, clinical study. Patients diagnosed with non-muscle invasive bladder cancer (Ta and T1) pathologically and suitable for TUR were enrolled randomly into two groups. In the study group, the patients received intravesical instillation within 24-hour post TURBT, followed by regular intravesical therapy using 30 mg/50 ml of THP(®) once a week for 8 weeks, and then once a month to 1 year postoperatively Among the patients. In the control group, patients received regular instillation only. RESULTS:A total of 403 patients were enrolled into this study from 26 institutions in China. Among the potients, 210 were enrolled into the study group and 193 were enrolled into the control group. At the median follow-up of 18 months, the recurrence rate was 7.8% in the study group, significantly lower than that in the control group (14.3%; P = 0.042). Subgroup analysis showed that the recurrence rate in low and intermediate-risk patients was significantly lower in the study group (6.8%) than in the control group (14.0%; P = 0.047), although no significant differences were found in high-risk patients. CONCLUSION:One immediate dose of THP(®) 30 mg after TURBT followed by regular intravesical therapy appears well tolerated and more effective than regular intravesical therapy for preventing tumor recurrence, especially in low and intermediate-risk patients.
    Extended vs non-extended pelvic lymph node dissection and their influence on recurrence-free survival in patients undergoing radical cystectomy for bladder cancer: a systematic review and meta-analysis of comparative studies. Bi Liangkuan,Huang Hai,Fan Xinxiang,Li Kaiwen,Xu Kewei,Jiang Chun,Liu Hao,Dong Wen,Zhang Simin,Yang Xiangyun,Lin Tianxin,Huang Jian BJU international OBJECTIVE:To compare extended pelvic lymph node dissection (ePLND) with non-extended pelvic lymph node dissection (non-ePLND) and assess their influence on recurrence-free survival (RFS) in patients undergoing radical cystectomy for bladder cancer. METHODS:Through a comprehensive search of the PubMed, Embase and Cochrane Library databases in September 2012, we performed a systematic review and cumulative meta-analysis of all comparative studies assessing the extent of pelvic lymph node dissection (PLND) and its influence on RFS. RESULTS:Six studies with a total of 2824 patients were identified. Overall analysis showed a significantly better RFS rate in patients who had undergone ePLND than in those who had undergone non-ePLND (hazard ratio [HR]: 0.65; P < 0.001). A subgroup analysis found that, compared with non-ePLND, ePLND was associated with a better RFS rate for both patients with negative lymph nodes (HR: 0.68; P = 0.007) and those with positive lymph nodes (HR: 0.58; P < 0.001). When stratified by pathological T stage, ePLND provided additional RFS benefits for patients with pT3-4 disease (HR: 0.61; P < 0.001), but not for patients with ≤pT2 disease (HR: 0.95; P = 0.81). CONCLUSIONS:The results of this meta-analysis indicate that ePLND provides a RFS benefit compared with non-ePLND. On subgroup analysis, ePLND provides better RFS not only for patients who had positive lymph nodes and pT3-4 disease, but also for patients with negative lymph nodes. Two randomized controlled trials on ePLND vs non-ePLND are awaited which should provide more clinically meaningful results. 10.1111/bju.12371
    MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3. Huang Li,Luo Junhua,Cai Qingqing,Pan Qiuhui,Zeng Hong,Guo Zhenghui,Dong Wen,Huang Jian,Lin Tianxin International journal of cancer Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to tumorigenesis. microRNA-125b (miR-125b) was implicated to have close relationship with cell proliferation and differentiation, and downregulation of miR-125b was observed in various types of cancers. However, the biological function of miR-125b in bladder tumorigenesis is still unknown. In our study, we showed that the expression of miR-125b was significantly decreased in bladder cancer tissues and four bladder cancer cell lines. Moreover, miR-125b could suppress bladder cancer cells to form colonies in vitro and to develop tumors in nude mice. E2F3, which was critical for G1/S transition and was overexpressed in most of poor-differentiated bladder cancers, was identified as a target of miR-125b by luciferase assay. The E2F3 mRNA and protein expression levels were detected in bladder cancer tissues and cell lines, and interestingly, inverse correlations between miR-125b and E2F3 protein level were found in bladder cancer tissues and four E2F3 nonamplified cell lines. Introduction of miR-125b could reduce the expression of E2F3 protein but not the E2F3 mRNA. In addition, we observed that transfection of miR-125b could inhibit the expression of Cyclin A2, one of the E2Fs-responsive genes involved in G1/S transition. These results suggest that miR-125b may regulate G1/S transition through the E2F3-Cyclin A2 signaling pathway. Taken together, miR-125b may act as a tumor suppressor in bladder urothelium, and downregulation of miR-125b may contribute to the tumorigenesis of bladder cancer. 10.1002/ijc.25509
    Development of a noninvasive tool to preoperatively evaluate the muscular invasiveness of bladder cancer using a radiomics approach. Zheng Junjiong,Kong Jianqiu,Wu Shaoxu,Li Yong,Cai Jinhua,Yu Hao,Xie Weibin,Qin Haide,Wu Zhuo,Huang Jian,Lin Tianxin Cancer BACKGROUND:Bladder cancer (BCa) can be divided into muscle-invasive BCa (MIBC) and non-muscle-invasive BCa (NMIBC). Whether the tumor infiltrates the detrusor muscle is a critical determinant of disease management in patients with BCa. However, the current preoperative diagnostic accuracy of muscular invasiveness is less than satisfactory. The authors report a radiomic-clinical nomogram for the individualized preoperative differentiation of MIBC from NMIBC. METHODS:In total, 2602 radiomics features were extracted from whole bladder tumors and the basal part of the lesions on T2-weighted magnetic resonance imaging. Then, a radiomics signature was constructed using the least absolute shrinkage and selection operator algorithm in the training set (n = 130). Furthermore, a radiomic-clinical nomogram was developed incorporating the radiomics signature and selected clinical predictors based on a multivariable logistic regression analysis. The performance of the nomogram (discrimination, calibration, and clinical usefulness) was assessed and validated in an independent validation set (n = 69). RESULTS:The radiomics signature, consisting of 23 selected features, showed good discrimination in the training and validation sets (area under the curve [AUC], 0.913 and 0.874, respectively). Incorporating the radiomics signature and magnetic resonance imaging-determined tumor size, the radiomic-clinical nomogram showed favorable calibration and discrimination in the training set with an AUC of 0.922, which was confirmed in the validation set (AUC, 0.876). Decision curve analysis and net reclassification improvement and integrated discrimination improvement indices (net reclassification improvement, 0.338, integrated discrimination improvement, 0.385) demonstrated the clinical usefulness of the nomogram. CONCLUSIONS:The proposed noninvasive radiomic-clinical nomogram can increase the accuracy of preoperatively discriminating MIBC from NMIBC, which may aid in clinical decision making and improve patient prognosis. 10.1002/cncr.32490
    A microRNA-7 binding site polymorphism in HOXB5 leads to differential gene expression in bladder cancer. Luo Junhua,Cai Qingqing,Wang Wei,Huang Hui,Zeng Hong,He Wang,Deng Weixi,Yu Hao,Chan Eddie,Ng Chi-fai,Huang Jian,Lin Tianxin PloS one PURPOSE:To investigate the biological function of HOXB5 in human bladder cancer and explore whether the HOXB5 3'-UTR SNP (1010A/G), which is located within the microRNA-7 binding site, was correlated with clinical features of bladder cancer. METHODS:Expression of HOXB5 in 35 human bladder cancer tissues and 8 cell lines were examined using real-time PCR and immunohistochemistry. Next, we explored the biological function of HOXB5 in vitro using cell proliferation, migration and colony formation assays. Using bioinformatics, a SNP (1010A/G) was found located within the microRNA-7 binding site in the 3'-UTR of HOXB5. Real-time PCR was used to test HOXB5 expression affected by different alleles. Finally, multivariate logistic regression analysis was used to determine the relationship between SNP (1010A/G) frequency and clinical features in 391 cases. RESULTS:HOXB5 was frequently over-expressed both in bladder cancer tissues and cell lines. Inhibition of HOXB5 suppressed the oncogenic function of cancer cells. Next, we demonstrated that a SNP (1010A/G), located within the microRNA-7 binding site in the 3'-UTR of HOXB5, could affect HOXB5 expression in bladder cancer mainly by differential binding activity of microRNA-7 and SNP-related mRNA stability. Finally, we also showed the frequency of 1010G genotype was higher in cancer group compared to normal controls and correlated with the risk of high grade and high stage. CONCLUSION:HOXB5 is overexpressed in bladder cancer. A miRNA-binding SNP (1010A/G) located within 3'-UTR of HOXB5 is associated with gene expression and may be a promising prognostic factor for bladder cancer. 10.1371/journal.pone.0040127
    A Radiomics Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer. Wu Shaoxu,Zheng Junjiong,Li Yong,Yu Hao,Shi Siya,Xie Weibin,Liu Hao,Su Yangfan,Huang Jian,Lin Tianxin Clinical cancer research : an official journal of the American Association for Cancer Research To develop and validate a radiomics nomogram for the preoperative prediction of lymph node (LN) metastasis in bladder cancer. A total of 118 eligible bladder cancer patients were divided into a training set ( = 80) and a validation set ( = 38). Radiomics features were extracted from arterial-phase CT images of each patient. A radiomics signature was then constructed with the least absolute shrinkage and selection operator algorithm in the training set. Combined with independent risk factors, a radiomics nomogram was built with a multivariate logistic regression model. Nomogram performance was assessed in the training set and validated in the validation set. Finally, decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the nomogram. The radiomics signature, consisting of nine LN status-related features, achieved favorable prediction efficacy. The radiomics nomogram, which incorporated the radiomics signature and CT-reported LN status, also showed good calibration and discrimination in the training set [AUC, 0.9262; 95% confidence interval (CI), 0.8657-0.9868] and the validation set (AUC, 0.8986; 95% CI, 0.7613-0.9901). The decision curve indicated the clinical usefulness of our nomogram. Encouragingly, the nomogram also showed favorable discriminatory ability in the CT-reported LN-negative (cN0) subgroup (AUC, 0.8810; 95% CI, 0.8021-0.9598). The presented radiomics nomogram, a noninvasive preoperative prediction tool that incorporates the radiomics signature and CT-reported LN status, shows favorable predictive accuracy for LN metastasis in patients with bladder cancer. Multicenter validation is needed to acquire high-level evidence for its clinical application. . 10.1158/1078-0432.CCR-17-1510
    Development and Validation of an MRI-Based Radiomics Signature for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer. Wu Shaoxu,Zheng Junjiong,Li Yong,Wu Zhuo,Shi Siya,Huang Ming,Yu Hao,Dong Wen,Huang Jian,Lin Tianxin EBioMedicine BACKGROUND:Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). However, a proportion of patients are at high risk for inaccurate clinical nodal staging by current methods. Here, we report an accurate magnetic resonance imaging (MRI)-based radiomics signature for the individual preoperative prediction of LN metastasis in BCa. METHODS:In total, 103 eligible BCa patients were divided into a training set (n = 69) and a validation set (n = 34). And 718 radiomics features were extracted from the cancerous volumes of interest (VOIs) on T2-weighted MRI images. A radiomics signature was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm in the training set, whose performance was assessed and then validated in the validation set. Stratified analyses were also performed. Based on the multivariable logistic regression analysis, a radiomics nomogram was developed incorporating the radiomics signature and selected clinical predictors. Discrimination, calibration and clinical usefulness of the nomogram were assessed. FINDINGS:Consisting of 9 selected features, the radiomics signature showed a favorable discriminatory ability in the training set with an AUC of 0.9005, which was confirmed in the validation set with an AUC of 0.8447. Encouragingly, the radiomics signature also showed good discrimination in the MRI-reported LN negative (cN0) subgroup (AUC, 0.8406). The nomogram, consisting of the radiomics signature and the MRI-reported LN status, showed good calibration and discrimination in the training and validation sets (AUC, 0.9118 and 0.8902, respectively). The decision curve analysis indicated that the nomogram was clinically useful. INTERPRETATION:The MRI-based radiomics nomogram has the potential to be used as a non-invasive tool for individualized preoperative prediction of LN metastasis in BCa. External validation is further required prior to clinical implementation. 10.1016/j.ebiom.2018.07.029
    Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis. Bi Junming,Liu Hongwei,Cai Zijian,Dong Wei,Jiang Ning,Yang Meihua,Huang Jian,Lin Tianxin Aging Circ-BPTF (hsa_circ_0000799) is a novel circular RNA derived from BPTF exons. Although BPTF is a well-studied predecessor gene, the characteristics and functions of circ-BPTF have not yet been reported. Here, we show that expression of circ-BPTF is increased in bladder cancer (BCa) tissues and cell lines compared with noncancerous tissues and cell lines. Consistently, BCa patients with higher expression levels of circ-BPTF were found to have higher tumor grades and poorer prognosis. Functionally, knockdown of circ-BPTF inhibited tumor progression in vitro and in vivo. Mechanistically, a target microRNA of circ-BPTF was confirmed to be miR-31-5p, and miR-31-5p mimics partially reversed the effect of circ-BPTF. Furthermore, RAB27A was predicted and shown to be a target of miR-31-5p, and circ-BPTF attenuated the anti-oncogenic effect of miR-31-5p and consequently enhanced RAB27A expression. In summary, our findings reveal that circ-BPTF promotes BCa progression through the miR-31-5p/RAB27A axis, suggesting that circ-BPTF may be a potential target for BCa treatment. 10.18632/aging.101520
    Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium. Lin Tianxin,Li Kaiwen,Liu Hao,Xue Xueyi,Xu Ning,Wei Yong,Chen Zhiwen,Zhou Xiaozhou,Qi Lin,He Wei,Tong Shiyu,Jin Fengshuo,Liu Xudong,Wei Qiang,Han Ping,Gou Xin,He Weiyang,Zhang Xu,Yang Guoqiang,Shen Zhoujun,Xu Tianyuan,Xie Xin,Xue Wei,Cao Ming,Yang Jin,Hu Jianyun,Chen Fubao,Li Peijun,Li Guangyong,Xu Tong,Tian Ye,Wang Wenying,Song Dongkui,Shi Lei,Yang Xiaoming,Yang Yang,Shi Benkang,Zhu Yaofeng,Liu Xigao,Xing Jinchun,Wu Zhun,Zhang Kaiyan,Li Wei,Liang Chaozhao,Yang Cheng,Li Wei,Qi Jinchun,Xu Chuanliang,Xu Weidong,Zhou Liqun,Cai Lin,Xu En'ci,Cai Weizhong,Weng Minggao,Su Yiming,Zhou Fangjian,Jiang Lijuan,Liu Zhuowei,Chen Qiuhong,Pan Tiejun,Liu Bo,Zhou Yu,Gao Xin,Qiu Jianguang,Situ Jie,Hu Cheng,Chen Shan,Zheng Yupeng,Huang Jian World journal of urology PURPOSE:Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS:From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS:There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS:ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation. 10.1007/s00345-017-2108-3
    Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM. Xie Ruihui,Chen Xu,Chen Ziyue,Huang Ming,Dong Wen,Gu Peng,Zhang Jingtong,Zhou Qianghua,Dong Wei,Han Jinli,Wang Xisheng,Li Hui,Huang Jian,Lin Tianxin Cancer letters Lymph node (LN) metastasis is the leading cause of bladder cancer-related mortality. Splicing factors facilitate cancer progression by modulating oncogenic variants, but it is unclear whether and how splicing factors regulate bladder cancer LN metastasis. In this study, Polypyrimidine tract binding protein 1 (PTBP1) expression was found to relate to bladder cancer LN metastasis, and was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that PTBP1 promoted bladder cancer cell migration, invasion, and proliferation in vitro, as well as LN metastasis and tumor growth in vivo. Mechanistic investigations revealed that PTBP1 upregulated MEIS2-L variant to promote metastasis and increased expression of PKM2 variant to enhance proliferation by modulating alternative mRNA splicing. Moreover, overexpression of MEIS2-L or PKM2 could rescue the oncogenic abilities of bladder cancer cells and the expression of MMP9 or CCND1 respectively after PTBP1 knockdown. In conclusion, our data demonstrate that PTBP1 induces bladder cancer LN metastasis and proliferation through an alternative splicing mechanism. PTBP1 may serve as a novel prognostic marker and therapeutic target for LN-metastatic bladder cancer. 10.1016/j.canlet.2019.01.041
    Current status of diagnosis and treatment of bladder cancer in China - Analyses of Chinese Bladder Cancer Consortium database. Li Kaiwen,Lin Tianxin, ,Xue Wei,Mu Xin,Xu Enci,Yang Xu,Chen Fubao,Li Guangyong,Ma Lulin,Wang Guoliang,Liang Chaozhao,Shi Haoqiang,Li Ming,Tang Mao,Xue Xueyi,Lv Yisong,Deng Yaoliang,Li Chengyang,Chen Zhiwen,Zhou Xiaozhou,Jin Fengshuo,Liu Xudong,Wei Jinxin,Shi Lei,Gou Xin,He Weiyang,Zhou Liqun,Cai Lin,Jin Baiye,Fu Guanghou,Kong Xiangbo,Sun Hongyan,Tian Ye,Feng Lang,Pan Tiejun,Wu Yiyi,Wang Dongwen,Hao Hailong,Shi Benkang,Zhu Yaofeng,Wei Qiang,Han Ping,Wu Changli,Tian Dawei,Ye Zhangqun,Liu Zheng,Wang Zhiping,Tian Junqiang,Qi Lin,Chen Minfeng,Li Wei,Qi Jinchun,Wang Gongxian,Fu Longlong,Sun Zhaolin,Luo Guangheng,Shen Zhoujun,Zhu Zhaowei,Xing Jinchun,Wu Zhun,Wei Dong,Chen Xin,Na Yanqun,Guo Hongfeng,Wang Chunxi,Lu Zhihua,Kong Chuize,Liu Yang,Yang Jin,Hu Jianyun,Gao Xin,Li Jielin,Yin Changjun,Li Pu,Chen Shan,Du Zhen,Li Jiongming,Yan Yongji,Zhang Xu,Huang Shuang,Zhou Fangjian,Zhang Zhiling,Sun Yinghao,Zeng Shuxiong,Cen Song,Zhou Jiaquan,Li Hanzhong,Wen Jin,Huang Jian Asian journal of urology Objective:To investigate current status of diagnosis and treatment of bladder cancer in China. Methods:A database was generated by Chinese Bladder Cancer Consortium (CBCC). From January 2007 to December 2012, 14,260 cases from 44 CBCC centers were included. Data of diagnosis, treatment and pathology were collected. Results:The average age was 63.5 year-old and most patients were male (84.3%). The most common histologic types were urothelial carcinoma (91.4%), adenocarcinoma (1.8%), and squamous carcinoma (1.9%). According to 1973 and 2004 WHO grading system, 42.0%, 41.0%, and 17.0% of patients were grade 1, 2, and 3, and 16.0%, 48.7%, and 35.3% of patients were papillary urothelial neoplasms of low malignant potential, low, and high grade, respectively. Non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) were 25.2% and 74.1%, respectively (0.8% not clear). Carcinoma was only 2.4%. Most patients were diagnosed by white-light cystoscopy with biopsy (74.3%). Fluorescence and narrow band imaging cystoscopy had additional detection rate of 1.0% and 4.0%, respectively. Diagnostic transurethral resection (TUR) provided detection rate of 16.9%. Most NMIBCs were treated with TUR (89.2%). After initial TUR, 2.6% accepted second TUR, and 45.7%, 69.9%, and 58.7% accepted immediate, induced, and maintenance chemotherapy instillation, respectively. Most MIBCs were treated with radical cystectomy (RC, 59.7%). Laparoscopic RCs were 35.1%, while open RC 63.4%. Extended and standard pelvic lymph node dissection were 7% and 66%, respectively. Three most common urinary diversions were orthotopic neobladder (44%), ileal conduit (31%), and ureterocutaneostomy (23%). Only 2.3% of patients accepted neo-adjuvant chemotherapy and only 18% of T3 and T4 patients accepted adjuvant chemotherapy. Conclusion:Disease characteristics are similar to international reports, while differences of diagnosis and treatment exist. This study can provide evidences for revisions of the guideline on bladder cancer in China. 10.1016/j.ajur.2015.04.016
    The landscape of chimeric RNAs in bladder urothelial carcinoma. Zhu Dingjun,Singh Sandeep,Chen Xu,Zheng Zaosong,Huang Jian,Lin Tianxin,Li Hui The international journal of biochemistry & cell biology BACKGROUND:Gene fusions and products have been identified as oncogenic drivers in many cancers, making them attractive diagnostic markers and therapeutic targets. However, the landscape of fusion transcripts in bladder cancer has not been fully characterized. METHODS:To identify fusion transcripts with potential therapeutic or diagnostic values, TCGA bladder urothelial carcinoma RNA-sequencing dataset was used. In order to avoid false positives, we applied multiple criteria including filtering out fusions detected in normal samples from GTEx dataset. We validated a subset of candidate fusions with a collection of bladder cancer and adjacent normal samples. RESULT:We identified 19,547 high confidence fusion genes from 414 bladder cancer samples. After filtering off M/M fusions, fusions in GTEx normal samples, and occurrence frequency <5, we obtained a list of 271 gene fusions, 13 of which were novel and specific to cancer samples. Six of those fusions were validated using cell lines and clinical samples. We discovered that two chimeric RNAs, BCL2L2-PABPN1 and CHFR-GOLGA3, were detected to be expressed significantly higher in bladder cancer samples compared to adjacent normal samples. Impressively, the wild-type of the parental genes were not differentially expressed. Mechanistically, we demonstrated that these two fusions are generated by cis-splicing between adjacent genes. These two fusions were detected mainly in the fraction of cell nucleus, suggesting a potential long noncoding RNA role. CONCLUSION:Our findings provide a panoramic view of the landscape of chimeric RNAs in bladder cancer. Some frequent chimeric RNAs are generated by intergenic splicing, and represent a new repertoire for potential biomarkers. 10.1016/j.biocel.2019.02.007
    Knockdown of a novel lincRNA AATBC suppresses proliferation and induces apoptosis in bladder cancer. Zhao Fengjin,Lin Tianxin,He Wang,Han Jinli,Zhu Dingjun,Hu Kaishun,Li Weicong,Zheng Zaosong,Huang Jian,Xie Wenlian Oncotarget Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating various biological processes in cancer, including proliferation and apoptosis. However, the roles of lincRNAs in bladder cancer remain elusive. In this study, we identified a novel lincRNA, which we termed AATBC. We found that AATBC was overexpressed in bladder cancer patient tissues and positively correlated with tumor grade and pT stage. We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb. In addition, inhibition of AATBC induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-9 and caspase-3. The investigation for the signaling pathway revealed that the apoptosis following AATBC knockdown was mediated by activation of phosphorylated JNK and suppression of NRF2. Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis. Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo. Taken together, our study indicated that AATBC might play a critical role in pro-proliferation and anti-apoptosis in bladder cancer by regulating cell cycle, intrinsic apoptosis signaling, JNK signaling and NRF2. AATBC could be a potential therapeutic target and molecular biomarker for bladder cancer. 10.18632/oncotarget.2833
    linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. He Wang,Cai Qingqing,Sun Fenyong,Zhong Guangzheng,Wang Pei,Liu Hongyan,Luo Junhua,Yu Hao,Huang Jian,Lin Tianxin Biochimica et biophysica acta OBJECTIVES:The human genome encodes many long intergenic noncoding RNAs (lincRNAs). However, their biological functions, molecular mechanisms and prognostic values associated with bladder cancer remain to be elucidated. Here we investigated a lincRNA termed linc-UBC1 (Up-regulated in bladder cancer 1) and evaluated its prognostic value in bladder cancer patients. MATERIALS AND METHODS:Expression of linc-UBC1 was evaluated by quantitative reverse transcription PCR (qRT-PCR) in 102 bladder cancer tissue samples and normal adjacent tissues. The functions of linc-UBC1 on cell proliferation, migration, invasion, colony formation, tumorigenicity and metastatic potential were evaluated by knockdown strategy in vitro and in vivo. RNA immunoprecipitation (RIP) was performed to confirm that linc-UBC1 physically associates with EZH2 and SUZ12, core components of polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation (ChIP) was conducted to examine histone modification status. RESULTS:qRT-PCR confirmed that linc-UBC1 expression is up-regulated in 60 cases (58.8%) in bladder cancer tissues compared with normal adjacent tissues, and its overexpression correlates with lymph node metastasis and poor survival. Further functional analysis demonstrated that knockdown of linc-UBC1 attenuates bladder cancer cell proliferation, motility, invasion, colony formation ability, tumorigenicity and metastatic potential. Importantly, the inhibitory effect of linc-UBC1 on cell proliferation was also observed in primary bladder cancer cells obtained from patients. RIP and ChIP assay confirmed that linc-UBC1 physically associates with PRC2 complex and regulates histone modification status of target genes. CONCLUSIONS:Frequently overexpressed linc-UBC1 physically associates with PRC2 complex, and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. 10.1016/j.bbadis.2013.05.010
    LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment. Chen Changhao,He Wang,Huang Jian,Wang Bo,Li Hui,Cai Qingqing,Su Feng,Bi Junming,Liu Hongwei,Zhang Bin,Jiang Ning,Zhong Guangzheng,Zhao Yue,Dong Wen,Lin Tianxin Nature communications Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1-induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1-modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer. 10.1038/s41467-018-06152-x
    Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation. Chen Xu,Xie Weibin,Gu Peng,Cai Qingqing,Wang Bo,Xie Yun,Dong Wen,He Wang,Zhong Guangzheng,Lin Tianxin,Huang Jian Scientific reports WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription; however, its role in bladder cancer remains largely unknown. Our study investigated the role of WDR5 in bladder cancer and demonstrated that WDR5 was upregulated in bladder cancer tissues, and elevated WDR5 protein levels positively correlated with advanced tumor stage and poor survival. Through gain or loss of function, we demonstrated that WDR5 promoted proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro, and tumor growth in vivo. Mechanistically, WDR5 regulated various functions in bladder cancer by mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1, BIRC3 and Nanog by histone H3 lysine 4 trimethylation. Therefore, we have discovered that WDR5 plays an important role in bladder cancer suggesting that WDR5 is a potential biomarker and a promising target in the treatment of bladder cancer. 10.1038/srep08293
    PBRM1 suppresses bladder cancer by cyclin B1 induced cell cycle arrest. Huang Li,Peng Yang,Zhong Guangzheng,Xie Weibin,Dong Wen,Wang Bo,Chen Xu,Gu Peng,He Wang,Wu Shaoxu,Lin Tianxin,Huang Jian Oncotarget Growing evidence indicates that dys-regulation of PBRM1 contributes to tumorigenesis. However, little is known about the biological function of PBRM1 in the development or progression of bladder cancer. In this study, we aimed to elucidate the pathophysiological role of PBRM1 in bladder cancer. We assessed the expression of PBRM1 in 64 bladder cancer tissue samples with matching normal tissues. We explored the biological functions of PBRM1 both in vitro and in vivo. Mutational status of PBRM1 was analyzed. Effect of PBRM1 on cell cycle was evaluated. qRT-PCR and Western blot were carried out to evaluate the expression of cyclins affected by PBRM1. Our results showed that PBRM1 expression was significantly reduced in bladder cancer cells and tissues compared to their normal counterparts. The reduced expression of PBRM1 was associated with advanced tumor stage, low differentiation grade and worse patient outcome. Further functional analysis demonstrated that PBRM1 suppressed bladder cancer cell proliferation, migration, colony formation in vitro and tumorigenicity in vivo. Genetic alteration analysis showed no amino-acid sequence altering mutations. We found that PBRM1 could block the G2/M transition by repressing cyclin B1. Our data indicated that PBRM1 functions as a tumor suppressor in bladder cancer by repressing cyclin B1 expression. 10.18632/oncotarget.3879
    DANCR Promotes Metastasis and Proliferation in Bladder Cancer Cells by Enhancing IL-11-STAT3 Signaling and CCND1 Expression. Chen Ziyue,Chen Xu,Xie Ruihui,Huang Ming,Dong Wen,Han Jinli,Zhang Jingtong,Zhou Qianghua,Li Hui,Huang Jian,Lin Tianxin Molecular therapy : the journal of the American Society of Gene Therapy The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. In this study, we discover that DANCR was significantly upregulated in BCa tissues and cases with LN metastasis. DANCR expression was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that DANCR promoted BCa cell migration, invasion, and proliferation in vitro and enhanced tumor LN metastasis and growth in vivo. Mechanistic investigations revealed that DANCR activated IL-11-STAT3 signaling and increased cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA. Moreover, oncogenesis facilitated by DANCR was attenuated by anti-IL-11 antibody or a STAT3 inhibitor (BP-1-102). In conclusion, our findings indicate that DANCR induces BCa LN metastasis and proliferation via an LRPPRC-mediated mRNA stabilization mechanism. DANCR may serve as a multi-potency target for clinical intervention in LN-metastatic BCa. 10.1016/j.ymthe.2018.12.015
    Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer. Liu Hongwei,Chen Dongliang,Bi Junming,Han Jinli,Yang Meihua,Dong Wei,Lin Tianxin,Huang Jian Aging Circular RNAs (circRNAs) have recently been confirmed to participate in different pathological processes, including cancer progression. However, the role and precise mechanism of action of the majority of circRNAs have not been elucidated in bladder cancer (BC). Here, we identified a novel circular RNA, termed circUBXN7, which was significantly downregulated in BC tissues compared with matched nontumor tissues. Importantly, we found that decreased circUBXN7 expression was associated with pathological stage, grade and poor prognosis of BC patients. Functional experiments showed that circUBXN7 overexpression dramatically inhibited proliferation, migration and invasion and suppressed tumor growth . Mechanistically, circUBXN7 could directly bind to miR-1247-3p and reverse the oncogenic effects induced by miR-1247-3p. Furthermore, B4GALT3 was predicted and confirmed to be a target of miR-1247-3p. Rescue experiments demonstrated that circUBXN7 abrogated miR-1247-3p-mediated inhibition of B4GALT3 expression. Finally, silencing of B4GALT3 promoted proliferation and invasion of BC cells; and partially abolished the tumor suppressive effects caused by circUBXN7. Taken together, our study revealed that circUBXN7 serves as a competitive endogenous RNA of miR-1247-3p to elevate B4GALT3 expression, consequently inhibiting cell viability and invasion in BC. The circUBXN7-miR-1247-3p-B4GALT3 regulatory network may provide a new perspective for gene-based treatment strategies for BC. 10.18632/aging.101573
    MicroRNA-155 promotes bladder cancer growth by repressing the tumor suppressor DMTF1. Peng Yang,Dong Wen,Lin Tian-Xin,Zhong Guang-Zheng,Liao Bei,Wang Bo,Gu Peng,Huang Li,Xie Yun,Lu Fu-Ding,Chen Xu,Xie Wei-Bin,He Wang,Wu Shao-Xu,Huang Jian Oncotarget MicroRNA-155 (miR-155) is dysregulated in human cancers. In this study, we reported that miR-155 was over-expressed in bladder cancer tissues. We found that miR-155 promoted cell proliferation in vitro and tumorigenesis in vivo. MiR-155 directly reduced the expression of the tumor suppressor DMTF1. The expression of DMTF1 was decreased in bladder cancer tissues. Similar to the restoring miR-155 expression, knockdown of DMTF1 promoted cell growth and cell cycle progression, whereas DMTF1 over-expression rescued the effect of miR-155. Moreover, we investigated DMTF1-Arf-p53 pathway and found that DMTF1 worked in both p53-dependent and p53-independent manners. Taken together, our findings suggested that miR-155 functions as a tumor promoter in bladder cancer, which is partially through repressing DMTF1 expression. The identification of miR-155 and its novel target DMTF1 will be valuable in developing diagnostic markers and therapeutic applications for bladder cancer. 10.18632/oncotarget.3755
    A Genomic-clinicopathologic Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer. Wu Shao-Xu,Huang Jian,Liu Zhuo-Wei,Chen Hai-Ge,Guo Pi,Cai Qing-Qing,Zheng Jun-Jiong,Qin Hai-De,Zheng Zao-Song,Chen Xin,Zhang Rui-Yun,Chen Si-Liang,Lin Tian-Xin EBioMedicine Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n=178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n=142; RJH set, n=104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients. 10.1016/j.ebiom.2018.03.034
    MicroRNA‑335 inhibits bladder cancer cell growth and migration by targeting mitogen‑activated protein kinase 1. Wang Xiaolin,Wu Guang,Cao Guangxin,Chen Xiaohong,Huang Jian,Jiang Xiaohui,Hou Jianquan Molecular medicine reports The abnormal expression of microRNAs (miRs) as oncogenes or tumor‑suppressor genes has been widely investigated in various tumor types. However, the roles of miR‑335 in bladder cancer cells have remained elusive. The aim of the present study was to assess the expression of miR‑335 in bladder cancer as well as the effects of miR‑335 on bladder cancer cell proliferation, metastasis and apoptosis. PCR and western blot analyses revealed that miR‑335 was significantly downregulated in bladder cancer tissues, and low levels of miR‑335 were associated with more aggressive phenotypes of bladder cancer. Overexpression of miR‑335 in T24 cells inhibited cell proliferation and induced apoptosis as indicated by an MTT assay and flow cytometric analysis, respectively. Furthermore, overexpression of miR‑335 significantly suppressed cell migration, as indicated by a Transwell assay. The expression of mitogen‑activated protein kinase (MAPK)1 was decreased after overexpression of miR‑335, indicating that MAPK1 may be a target gene of miR‑335. In addition, silencing of MAPK1 inhibited the proliferation and migration of bladder cancer cells. In conclusion, the results of the present study demonstrated that miR‑335 was significantly downregulated in bladder cancer, and may act as a tumor suppressor through repression of MAPK1. 10.3892/mmr.2016.5448
    Pirarubicin induces an autophagic cytoprotective response through suppression of the mammalian target of rapamycin signaling pathway in human bladder cancer cells. Li Kuiqing,Chen Xu,Liu Cheng,Gu Peng,Li Zhuohang,Wu Shaoxu,Xu Kewei,Lin Tianxin,Huang Jian Biochemical and biophysical research communications Pirarubicin is widely used in intravesical chemotherapy for bladder cancer, but its efficacy is limited due to drug resistance; the mechanism has not been well studied. Emerging evidence shows that autophagy can be a novel target for cancer therapy. This study aimed to investigate the role of autophagy in pirarubicin-treated bladder cancer cells. Bladder cancer cells EJ and J82 were treated with pirarubicin, siRNA, 3-methyladenine or hydroxychloroquine. Cell proliferation and apoptosis were tested by cell survival assay and flow cytometric analysis, respectively. Autophagy was evaluated by immunoblotting before and after the treatments. The phosphorylated mammalian target of rapamycin, serine/threonine kinase p70 S6 kinase, and eukaryotic translation initiation factor 4E binding protein 1 were also investigated by immunoblotting. We found that pirarubicin could induce autophagy in bladder cancer cells. Inhibition of autophagy by 3-methyladenine, hydroxychloroquine or knockdown of autophagy related gene 3 significantly increased apoptosis in pirarubicin-treated bladder cancer cells. Pirarubicin-induced autophagy was mediated via the mTOR/p70S6K/4E-BP1 signaling pathway. In conclusion, autophagy induced by pirarubicin plays a cytoprotective role in bladder cancer cells, suggesting that inhibition of autophagy may improve efficacy over traditional pirarubicin chemotherapy in bladder cancer patients. 10.1016/j.bbrc.2015.03.042
    Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis. Liu Hongwei,Bi Junming,Dong Wei,Yang Meihua,Shi Juanyi,Jiang Ning,Lin Tianxin,Huang Jian Molecular cancer BACKGROUND:Increasing evidence has revealed that circular RNAs (circRNAs) play crucial roles in cancer biology. However, the role and underlying regulatory mechanisms of circFNDC3B in bladder cancer (BC) remain unknown. METHODS:A cell invasion model was established by repeated transwell assays, and invasion-related circRNAs in BC were identified through an invasion model. The expression of circFNDC3B was detected in 82 BC tissues and cell lines by quantitative real-time PCR. Functional assays were performed to evaluate the effects of circFNDC3B on proliferation, migration and invasion in vitro-, and on tumorigenesis and metastasis in vivo. The relationship between circFNDC3B and miR-1178-3p was confirmed by fluorescence in situ hybridization, pull-down assay and luciferase reporter assay. RESULTS:In the present study, we identified a novel circRNA (circFNDC3B) through our established BC cell invasion model. We found that circFNDC3B was dramatically downregulated in BC tissues and correlated with pathological T stage, grade, lymphatic invasion and patients' overall survival rate. Functionally, overexpression of circFNDC3B significantly inhibited proliferation, migration and invasion both in vitro and in vivo. Mechanistically, circFNDC3B could directly bind to miR-1178-3p, which targeted the 5'UTR of the oncogene G3BP2. Moreover, circFNDC3B acted as a miR-1178-3p sponge to suppress G3BP2, thereby inhibiting the downstream SRC/FAK signaling pathway. CONCLUSIONS:CircFNDC3B may serve as a novel tumor suppressive factor and potential target for new therapies in human BC. 10.1186/s12943-018-0908-8
    The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1. Su Feng,He Wang,Chen Changhao,Liu Mo,Liu Hongwei,Xue Feiyuan,Bi Junming,Xu Dawei,Zhao Yue,Huang Jian,Lin Tianxin,Jiang Chun Cell death & disease Long non-coding RNAs (lncRNAs) have been identified as significant regulators in cancer progression. Positive feedback loops between lncRNAs and transcription factors have attracted increasing attention. Akt pathway plays a crucial role in bladder cancer growth and recurrence. In the present study, we demonstrate a novel regulatory pattern involving FOXD2-AS1, Akt, and E2F1. FOXD2-AS1 is highly expressed in bladder cancer and is associated with tumor stage, recurrence, and poor prognosis. Further experiments showed that FOXD2-AS1 promotes bladder cancer cell proliferation, migration, and invasion in vitro and in vivo. Microarray analysis demonstrated that FOXD2-AS1 negatively regulates the expression of Tribbles pseudokinase 3 (TRIB3), a negative regulator of Akt. Mechanistically, FOXD2-AS1 forms an RNA-DNA complex with the promoter of TRIB3, the transcriptional activity of which is subsequently repressed, and leads to the activation of Akt, which further increases the expression of E2F1, a vital transcription factor involved in the G/S transition. Interestingly, E2F1 could bind to the FOXD2-AS1 promoter region and subsequently enhance its transcriptional activity, indicating that FOXD2-AS1/Akt/E2F1 forms a feedback loop. In summary, this regulatory pattern of positive feedback may be a novel target for the treatment of bladder cancer and FOXD2-AS1 has the potential to be a new recurrence predictor. 10.1038/s41419-018-0275-9
    Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer. Chen Xu,Gu Peng,Xie Ruihui,Han Jinli,Liu Hao,Wang Bo,Xie Weibin,Xie Weijie,Zhong Guangzheng,Chen Changhao,Xie Shujie,Jiang Ning,Lin Tianxin,Huang Jian Journal of cellular and molecular medicine Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an essential RNA- and DNA-binding protein that regulates diverse biological events, especially DNA transcription. hnRNPK overexpression is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of hnRNPK in bladder cancer are unclear. We investigated hnRNPK expression by immunohistochemistry in 188 patients with bladder cancer, and found that hnRNPK expression levels were significantly increased in bladder cancer tissues and that high-hnRNPK expression was closely correlated with poor prognosis. Loss- and gain-of-function assays demonstrated that hnRNPK promoted proliferation, anti-apoptosis, and chemoresistance in bladder cancer cells in vitro, and hnRNPK knockdown suppressed tumorigenicity in vivo. Mechanistically, hnRNPK regulated various functions in bladder cancer by directly mediating cyclin D1, G0/G1 switch 2 (G0S2), XIAP-associated factor 1, and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) transcription. In conclusion, we discovered that hnRNPK plays an important role in bladder cancer, suggesting that it is a potential prognostic marker and a promising target for treating bladder cancer. 10.1111/jcmm.12999
    Comparative efficacy of vitamin D status in reducing the risk of bladder cancer: A systematic review and network meta-analysis. Zhao Yue,Chen Changhao,Pan Wenwei,Gao Ming,He Wang,Mao Ren,Lin Tianxin,Huang Jian Nutrition (Burbank, Los Angeles County, Calif.) OBJECTIVES:The optimal concentration of individual vitamin D intake for preventing bladder cancer has not, to our knowledge, been defined. To evaluate the comparative efficacy of different serum 25-hydroxyvitamin D concentrations in preventing bladder cancer, we conducted a systematic search of the literature published up to April 2015. METHODS:We applied a pairwise meta-analysis to estimate direct evidence from intervention-control studies and a network meta-analysis within a Bayesian framework to combine direct and indirect evidence. Moreover, a dose-response curve was utilized to predict the optimal median serum 25-hydroxyvitamin D concentration based on the odds ratio (OR) for each quintile concentration. METHODS:Seven studies of a total of 90757 participants, including 2509 bladder cancer patients, were included. Two prospective cohort studies with 57 591 participants and 494 bladder cancer patients, and five case-control studies with 33 166 participants and 2264 bladder cancer patients. From the network meta-analysis, we observed that sufficient serum 25-hydroxyvitamin D concentrations (>75 nmol/L) were superior to all other 25-hydroxyvitamin D concentrations in decreasing the risk of bladder cancer: OR = 0.68 and 95% credible interval (CrI) 0.52 to 0.87 compared with severely deficient concentrations (<25 nmol/L); OR = 0.65 and 95% CrI 0.49 to 0.86 compared with moderately deficient concentrations (25-37.5 nmol/L); OR = 0.61 and 95% CrI 0.47 to 0.80 compared with slightly deficient concentrations (37.5-50 nmol/L); and OR = 0.65 and 95% CrI 0.48 to 0.85 compared with insufficient concentrations (50-75 nmol/L). In addition, we noted a roughly inverse correlation between bladder cancer risk and 25-hydroxyvitamin D concentrations (R(2) = 0.98, P = 0.007). CONCLUSIONS:Ensuring sufficient serum 25-hydroxyvitamin D concentrations might play an important role in decreasing the risk of bladder cancer. The serum 25-hydroxyvitamin D concentration ≥74 nmol/L was associated with a 60% lower risk of bladder cancer incidence. 10.1016/j.nut.2015.10.023
    lncRNA Up-Regulated in Nonmuscle Invasive Bladder Cancer Facilitates Tumor Growth and Acts as a Negative Prognostic Factor of Recurrence. Zhang Simin,Zhong Guangzheng,He Wang,Yu Hao,Huang Jian,Lin Tianxin The Journal of urology PURPOSE:While lncRNAs (long noncoding RNAs) have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle invasive bladder cancer remain largely unknown. We identified a lncRNA termed lncRNA-UNMIBC (up-regulated in nonmuscle invasive bladder cancer) and evaluated its prognostic value in patients with primary nonmuscle invasive bladder cancer. MATERIALS AND METHODS:We analyzed the expression of lncRNA-UNMIBC in the tissues of 75 cases of primary nonmuscle invasive bladder cancer and adjacent normal mucosa by quantitative real-time polymerase chain reaction. Data were compared with clinicopathological parameters using the Kaplan-Meier method and multivariate Cox regression analysis. The functions of lncRNA-UNMIBC were assessed by silencing the lncRNA in vitro and in vivo. RNA immunoprecipitation was performed to assay whether lncRNA-UNMIBC could be physically associated with EZH2 (enhancer of zeste homolog 2) and SUZ12 (SUZ12 polycomb repressive complex 2 subunit), which are core components of PRC2 (polycomb repressive complex 2). Chromatin immunoprecipitation was done to examine histone modification status. RESULTS:The expression level of lncRNA-UNMIBC was up-regulated in the tissues of 45 cases of primary nonmuscle invasive bladder cancer compared with normal mucosa. Kaplan-Meier estimates showed that lncRNA-UNMIBC expression was significantly associated with recurrence (log rank test p = 0.0151). We also found that lncRNA-UNMIBC had a key role in G0/G1 arrest. Furthermore, RNA and chromatin immunoprecipitation assays demonstrated that lncRNA-UNMIBC was physically associated with EZH2 and SUZ12, leading to an altered histone H3 lysine 27 methylation status of target genes. CONCLUSIONS:These findings indicate that lncRNA-UNMIBC can facilitate tumor growth and may act as a negative prognostic factor of recurrence. 10.1016/j.juro.2016.05.107
    MALBAC-based chromosomal imbalance analysis: a novel technique enabling effective non-invasive diagnosis and monitoring of bladder cancer. Liu Hao,He Wang,Wang Bo,Xu Kewei,Han Jinli,Zheng Junjiong,Ren Jun,Shao Lin,Bo Shiping,Lu Sijia,Lin Tianxin,Huang Jian BMC cancer BACKGROUND:The gold standard for bladder cancer detection is cystoscopy, which is an invasive procedure that causes discomfort in patients. The currently available non-invasive approaches either show limited sensitivity in low-grade tumours or possess unsatisfying specificity. The aim of the present study is to develop a new non-invasive strategy based on chromosomal imbalance levels to detect bladder cancer effectively. METHODS:We enrolled 74 patients diagnosed with bladder cancer (BC), 51 healthy participants and 27 patients who were diagnosed with non-malignant urinary disease (UD). The Chromosomal Imbalance Analysis (CIA) was conducted in the tumours and urine of participants via the multiple annealing and looping-based amplification cycles-next-generation sequencing (MALBAC-NGS) strategy. The threshold of the CIA was determined with the receiver operating characteristic (ROC) curve. The comparison of the CIA with voided urine cytology was also performed in a subgroup of 55 BC patients. The consistency and discrepancy of the different assays were studied with the Kappa analysis and the McNemar test, respectively. The performance of the urinary CIA was also validated in an additional group of 120 BC patients, 15 UD and 45 healthy participants. RESULTS:Good concordance (87.0%) in the assessments of patient tumour tissues and urine was observed. The urine-based evaluation also demonstrated a good performance (accuracy = 89.0%, sensitivity = 83.1%, specificity = 94.5%, NPV = 85.4% and PPV = 93.7%; AUC = 0.917, 95%CI =0.868-0.966, P < 0.001) in the training group, particularly in the patients with CIA-positive tumours (accuracy = 92.7%, sensitivity = 89.8%). The sensitivity and specificity in the validation group were 89.2 and 90.0%, respectively. Even in Ta/T1 and low-grade tumour patients, the sensitivity was 85-90%. The CIA also exhibited a significantly improved sensitivity compared to voided urine cytology. CONCLUSIONS:This is the first study employing the concept of whole genome imbalance combined with the MALBAC technique to detect bladder cancer in urine. MALBAC-CIA yielded significant diagnostic power, even in early-stage/low-grade tumour patients, and it may be used as a non-invasive approach for diagnosis and recurrence surveillance in bladder cancer prior to the use of cystoscopy, which would largely reduce the burden on patients. 10.1186/s12885-018-4571-7
    Causes of death in long-term bladder cancer survivors: A population-based study. Kong Jianqiu,Diao Xiayao,Diao Feiyu,Fan Xinxiang,Zheng Junjiong,Yan Dong,Huang Jian,Qin Haide,Lin Tianxin Asia-Pacific journal of clinical oncology BACKGROUND:Long-term (> 5 years) bladder cancer survivors represent a distinct subgroup of bladder cancer patients and information about the causes of death in this subgroup is limited. The aim of this study was to review the causes of death in long-term bladder cancer survivors. METHOD:The Surveillance, epidemiology and end results (SEER) database was used to analyze the causes of death of long-term bladder cancer survivors. Patients' characteristics and survival outcomes were reported for the entire cohort in our study. Kaplan-Meier analysis and Cox proportional hazard model for survival analysis. RESULTS:A total of 147 781 bladder cancer patients with >5 years survival were identified. This cohort included 81 843 patients surviving 5-10 years and 65 938 patients surviving >10 years. Among the patients who survived 5-10 years, 6.9% died because of primary bladder cancer, 11.0% due to cardiac disease and 7.7% due to nonmalignant pulmonary disease. Among patients surviving >10 years, 3.1% died because of primary bladder cancer, 8.6% due to cardiac disease and 5.8% due to nonmalignant pulmonary disease. On multivariate analysis, factors associated with longer cardiac disease-specific survival among long-term bladder cancer survivors include younger age at diagnosis(<40 years; vs. 40-69 years, P = 0.030 or >69 years, P < 0.001), married status (vs. single status, P < 0.001), white race (vs. African American race, P = 0.002), male (vs. female, P < 0.001), grade I (vs. grade III, P = 0.003 or grade IV, P < 0.001). CONCLUSION:The probability of death from primary bladder cancer is still important among various causes of death even 20 years after being diagnosed with bladder cancer. Furthermore, cardiopulmonary causes contributed to a considerable proportion of deaths in long-term bladder cancer survivors. 10.1111/ajco.13156
    Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. He Wang,Zhong Guangzheng,Jiang Ning,Wang Bo,Fan Xinxiang,Chen Changhao,Chen Xu,Huang Jian,Lin Tianxin The Journal of clinical investigation The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer-associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer-associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti-VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer. 10.1172/JCI96218