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Positive expression of protein chromosome 9 open reading frame 86 (C9orf86) correlated with poor prognosis in non-small cell lung cancer patients. Peng Gui-Lin,Tao Ya-Lan,Wu Qi-Nian,Zhang Yu,He Jian-Xing Journal of thoracic disease BACKGROUND:Chromosome 9 open reading frame 86 (C9orf86) is a novel subfamily of GTPases. Previous studies have implicated C9orf86 as a potential oncogene. METHODS:C9orf86 expression was detected in non-small cell lung cancer (NSCLC) cell lines and human bronchial epithelial (16HBE) cell lines by RT-PCR and western blotting. Immunohistochemistry (IHC) was used to detect 180 consecutive NSCLC specimens and 16 normal lung tissues. The correlation between C9orf86 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox hazards ratio models were used to estimate the effect of C9orf86 expression on survival. RESULTS:C9orf86 was expressed in the cytoplasm in 74 of 180 (41.11%) NSCLC specimens. In clinical pathology analysis, C9orf86 expression significantly correlated with lymph node metastasis and clinical stage significantly (P<0.05). Multivariable analysis confirmed that C9orf86 expression increased the risk of death after adjusting for other clinicopathological factors (P<0.01). Overall survival (OS) and disease-free survival (DFS) were significantly prolonged in the C9orf86 negative group compared to the C9orf86 positive group (P<0.001). Adjuvant chemotherapy prolonged OS and DFS in resected NSCLC patients with C9orf86 negative expression (P<0.001) but not C9orf86 positive. CONCLUSIONS:Positive expression of C9orf86 is an independent prognostic factor for NSCLC patients, and C9orf86 may serve as a prognostic biomarker for patients with NSCLC. 10.21037/jtd.2016.04.70
Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance. Wu Qi-Nian,Liao Yi-Fu,Lu Yun-Xin,Wang Yun,Lu Jia-Huan,Zeng Zhao-Lei,Huang Qi-Tao,Sheng Hui,Yun Jing-Ping,Xie Dan,Ju Huai-Qiang,Xu Rui-Hua Cancer letters Gastric cancer (GC) is the second cause of cancer-related death. Cisplatin (CDDP) is widely used as the standard GC treatment, but relapse and metastasis are common because of intrinsic or acquired drug resistance. The mitogen-activated protein kinase phosphatases (MAPK)-extracellular signal regulated kinases (ERK) pathway contributes to GC progression and drug resistance, but targeting the MAPK-ERK pathway is challenging in GC therapy. Here, we demonstrated that dual-specificity phosphatases 6 (DUSP6) was overexpressed in GC and predicted poor overall survival and progression-free survival. Knockdown DUSP6 inhibited GC proliferation, migration, invasion and induced apoptosis. (E/Z)-BCI hydrochloride (BCI), a DUSP6 small molecule inhibitor, increased the activity of ERK but interestingly decreased the expression of ERK response genes in BGC823, SGC7901 and CDDP-resistant SGC7901/DDP cells. BCI also caused cell death through the DNA damage response (DDR) pathway. Moreover, BCI inhibited cell proliferation, migration and invasion in a receptor-independent manner and enhanced CDDP cytotoxicity at pharmacological concentrations in the GC cells. In vivo experiments further showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models. In summary, our findings indicated that disruption of DUSP6 by BCI enhanced CDDP-induced cell death and apoptosis in GC may partly through ERK and DDR pathways. Thus, this study suggests that DUSP6 is a potential prognostic biomarker and a promising target for GC therapy. 10.1016/j.canlet.2017.10.007
Elevated baseline serum lactate dehydrogenase indicates a poor prognosis in primary duodenum adenocarcinoma patients. Journal of Cancer Tumour cells produce energy through glycolysis and lactate dehydrogenase (LDH) is a key part of glycolysis. Elevation of serum LDH may indicate poor prognosis in primary duodenum adenocarcinoma. We aim to explore the prognostic significance of LDH in this disease. Two hundred forty-four patients diagnosed with primary duodenum adenocarcinoma who were treated at the Sun Yat-sen Cancer Center from February 1996 to January 2016 were retrospectively analysed. We collected routine clinical data, including baseline LDH. Patients were classified into a normal LDH group (≤ 245U/L) and higher LDH group (>245U/L). Correlations of the LDH level and other clinicopathological characteristics were explored using the Chi-square test. Prognostic factors for overall survival were identified using univariate and multivariate analyses. Two hundred seven patients (84.9%) had normal LDH levels, while 37 patients (15.1%) had abnormally high LDH levels. Higher LDH levels were significantly associated with more distant metastasis, node metastasis, poor differentiation and TNM stage Ⅲ-Ⅳ (P<0.05). Consistently, patients with node metastasis, poor differentiation and TNM stageⅢ-Ⅳ had a significantly higher median LDH level (P<0.05). The median survival of patients in the higher LDH group was significantly shorter than that of the patients in the normal LDH group (16.3 m vs. 42.5 m, =0.02). Using multivariate analysis, LDH, age and radical surgery were independent prognostic factors associated with overall survival(OS) (HR=1.571, =0.036 for LDH; HR=1.514, =0.013 for age; HR=0.248, <0.0001 for radical surgery, respectively). For the first time, our research suggests that baseline serum LDH is an independent prognostic factor in primary duodenum adenocarcinoma patients and elevated baseline serum LDH indicates a poor prognosis. 10.7150/jca.22305
Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation. Lu Yun-Xin,Wu Qi-Nian,Chen Dong-Liang,Chen Le-Zong,Wang Zi-Xian,Ren Chao,Mo Hai-Yu,Chen Ya,Sheng Hui,Wang Ying-Nan,Wang Yun,Lu Jia-Huan,Wang De-Shen,Zeng Zhao-Lei,Wang Feng,Wang Feng-Hua,Li Yu-Hong,Ju Huai-Qiang,Xu Rui-Hua Theranostics : The antitumor activity of high-dose ascorbate has been re-evaluated recently, but the mechanism underlying cell-specific sensitivity to ascorbate has not yet been clarified. The effects of high-dose ascorbate on gastric cancer were assessed using cancer cell lines with high and low expression of GLUT1 via flow cytometry and colony formation assays and patient-derived xenografts . : In this study, we demonstrated that gastric cancer cells with high GLUT1 expression were more sensitive to ascorbate treatment than cells with low GLUT1 expression. GLUT1 knockdown significantly reversed the therapeutic effects of pharmacological ascorbate, while enforced expression of GLUT1 enhanced the sensitivity to ascorbate treatment. The efficacy of pharmacological ascorbate administration in mice bearing cell line-based and patient-derived xenografts was influenced by GLUT1 protein levels. Mechanistically, ascorbate depleted intracellular glutathione, generated oxidative stress and induced DNA damage. The combination of pharmacological ascorbate with genotoxic agents, including oxaliplatin and irinotecan, synergistically inhibited gastric tumor growth in mouse models. : The current study showed that GLUT1 expression was inversely correlated with sensitivity of gastric cancer cells to pharmacological ascorbate and suggested that GLUT1 expression in gastric cancer may serve as a marker for sensitivity to pharmacological ascorbate. 10.7150/thno.21745
Hepatitis B virus infection is associated with younger median age at diagnosis and death in cancers. Wei Xiao-Li,Luo Hui-Yan,Li Chao-Feng,Jin Ying,Zeng Zhao-Lei,Ju Huai-Qiang,Wu Qi-Nian,Wang Yun,Mao Min-Jie,Liu Wan-Li,Jia Wei-Hua,Zhang Hui-Zhong,Li Yu-Hong,Wang Feng,Xu Rui-Hua International journal of cancer Several non-hepatocellular cancers were linked with hepatitis B virus (HBV) infection. This study was aimed to quantify the potential associations between HBV infection and multiple non-hepatocellular cancers. Continuous cases, including 5,715 non-cancer and 40,963 cancer cases diagnosed from 2008 to 2014 in Sun Yat-sen University Cancer Center were analyzed. HBV DNA and hepatitis B core antigen (HBcAg) were examed in gastric cancer tissues by polymerase chain reaction and immunohistochemical staining. After adjusting for age, sex, year of diagnosis, smoking, drinking and family history of cancer, significant associations were found between serum HBsAg and frequently reported HBV-related non-hepatocellular cancers, including non-Hodgkin's lymphoma, cholangiocarcinoma and pancreatic cancer [adjusted odds ratio (AOR) and 95% confidence interval (CI): 1.89 (1.65-2.16)], as well as total other non-hepatocellular cancers [AOR and 95% CI: 1.12 (1.03-1.22)]. The median ages at diagnosis, all-cause death and cancer-specific death of serum HBsAg positive cancer patients were all significantly younger than those with serum HBsAg negative. HBV DNA was detected in 12.4% (34/275) gastric cancer tissues and HBcAg was most commonly detected in lymphocytes. This was the first report that HBV infection had a modest but significant nonspecific association with total non-hepatocellular cancers. Median age at diagnosis and death was significantly younger in serum HBsAg positive cancer patients. The underlying mechanism needs further investigation. 10.1002/ijc.30719
Comparison of HER2 and Lauren Classification between Biopsy and Surgical Resection Samples, Primary and Metastatic Samples of Gastric Cancer. Qiu Miao-Zhen,Shi Si-Mei,Chen Min,Wang Jing,Wu Qi-Nian,Sheng Hui,Zhang Hui-Zhong,Yun Jing-Ping,Zhou Zhi-Wei,Wang Feng-Hua,Yang Da-Jun,Xu Rui-Hua Journal of Cancer Patients with advanced or metastatic adenocarcinoma of the stomach or esophagogastric junction for whom trastuzumab therapy is being considered, assessment for tumor human epidermal growth factor receptor-2 (HER2) status is necessary. Can the HER2 status and Lauren classification of the biopsy sample truly represent the HER2 status in the gastric cancer? Formalin-fixed, paraffin-embedded sections of 116 pair surgically resected and biopsy specimens as well as 80 pair primary and metastatic lesions of gastric cancer patients were analyzed. Protein expression was assessed using immunohistochemistry (IHC) and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH) in IHC 2+ cases. The positive rate of HER2 was 11.2% in both surgical and biopsy samples. The consistent rate of HER2 expression was 91.4% (106/116) between biopsy and surgical samples, P=0.666. The positive rate of HER2 was 20.5% in primary and 15.9% in metastatic samples, P=0.1876. The consistent rate of HER2 expression was 90.9% (40/44) between primary and metastatic samples, P=0.580. The consistent rate of Lauren classification was 64.7% (75/116) between biopsy and surgical sample, and 92.5% (74/80) between primary and metastatic samples. For gastric cancer, HER2 expression and Lauren classification were highly homogenous in biopsy and surgical samples, primary and their corresponding metastatic samples. The high concordance observed between these two cohorts indicated that the HER2 examination and Lauren classification of biopsy samples from the primary tumor could well represent the metastatic lesions of the patients. 10.7150/jca.19984
The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer. Wei Xiao-Li,Wu Qi-Nian,Chen Dong-Liang,Zeng Zhao-Lei,Lu Jia-Bin,Liu Ze-Xian,Ju Huai-Qiang,Ren Chao,Pan Zhi-Zhong,Wang Feng-Hua,Xu Rui-Hua Journal of Cancer Programmed death ligand 1 (PD-L1) expression has been shown to predict benefit from anti-PD-1 treatment in several cancers. However, its predictive value in colorectal cancer seems limited. This study was aimed to explore the clinical and biomarker association of programmed death ligand 1 and its spatial heterogeneous expression in colorectal cancer. Tissue microarrays of 422 primary colorectal cancers from our hospital were used for the interpretation of PD-L1 and programmed death 1 (PD-1) expression, cluster of differentiation 4 (CD4) and CD8 density and microsatellite instability (MSI) status by immunohistochemistry. To assess the spatial heterogeneity of PD-L1 expression, Tissue microarrays of 383 paired intra-primary-tumor tissues, and 105 paired lymph node metastatic tumors and 64 paired distant metastatic tumors were also used. PD-L1 was positive in 188 (44.5%) primary colorectal cancers. PD-L1 expression was associated with less advanced N category (<0.001), less advanced TNM stage (<0.001) and less nervous invasion (=0.04). Higher PD-L1 expression was associated with higher PD-1 expression (<0.001), higher CD4 (<0.001) and CD8 (<0.001) density and DNA mismatch repair deficiency (=0.01). PD-L1 expression was associated with better disease-free survival and overall survival, but it was only an independent prognostic factor for disease-free survival (hazard ratio and 95% confidence interval: 0.42 [0.25-0.72], <0.001). The probability of inconsistent PD-L1 expression was respectively 17.8%, 31.4% and 39.1% within primary tumors, between primary tumors and lymph node metastatic tumors, and between primary tumors and distant metastatic tumors. All the three differences were statistically significant (<0.001, <0.001 and =0.05, respectively). PD-L1 expression was a marker of pre-existing immune responses in colorectal cancer, however, it was heterogeneously expressed in colorectal cancer, especially between primary and metastatic tumors. This might partially explain the low-efficiency of its predictive value for benefit from anti-PD-1 treatment. 10.7150/jca.27735
CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. Wang Ying-Nan,Zeng Zhao-Lei,Lu Jiahuan,Wang Yun,Liu Ze-Xian,He Ming-Ming,Zhao Qi,Wang Zi-Xian,Li Ting,Lu Yun-Xin,Wu Qi-Nian,Yu Kai,Wang Feng,Pu Heng-Ying,Li Bo,Jia Wei-Hua,Shi Ming,Xie Dan,Kang Tie-Bang,Huang Peng,Ju Huai-Qiang,Xu Rui-Hua Oncogene Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC. 10.1038/s41388-018-0384-z
ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis. Lu Yun-Xin,Ju Huai-Qiang,Liu Ze-Xian,Chen Dong-Liang,Wang Yun,Zhao Qi,Wu Qi-Nian,Zeng Zhao-Lei,Qiu Hai-Bo,Hu Pei-Shan,Wang Zhi-Qiang,Zhang Dong-Sheng,Wang Feng,Xu Rui-Hua Cancer research Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that () is frequently hemizygously codeleted with in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer Intratumoral injection of siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis. These findings reveal the role of malic enzyme in growth and metastasis. http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg . 10.1158/0008-5472.CAN-17-3155
Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer. Chen Zhan-Hong,Qi Jing-Jing,Wu Qi-Nian,Lu Jia-Huan,Liu Ze-Xian,Wang Yun,Hu Pei-Shan,Li Ting,Lin Jin-Fei,Wu Xiang-Yuan,Miao Lei,Zeng Zhao-Lei,Xie Dan,Ju Huai-Qiang,Xu Rui-Hua,Wang Feng Journal of experimental & clinical cancer research : CR BACKGROUND:Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). METHODS:Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. RESULTS:EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. CONCLUSIONS:EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. 10.1186/s13046-019-1178-z
Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. Ju Huai-Qiang,Lu Yun-Xin,Chen Dong-Liang,Zuo Zhi-Xiang,Liu Ze-Xian,Wu Qi-Nian,Mo Hai-Yu,Wang Zi-Xian,Wang De-Shen,Pu Heng-Ying,Zeng Zhao-Lei,Li Bo,Xie Dan,Huang Peng,Hung Mien-Chie,Chiao Paul J,Xu Rui-Hua Journal of the National Cancer Institute BACKGROUND:Overcoming oxidative stress is a critical step for tumor progression; however, the underlying mechanisms in colorectal cancer (CRC) remain unclear. METHODS:We investigated nicotinamide adenine dinucleotide (phosphate) (NAD(P))-dependent enzyme methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, clinical relevance, redox modification, and molecular mechanisms using the CRC cells and tissues (n = 462 paired samples). The antitumor effects of MTHFD2 inhibitor LY345899 on CRC tumorigenesis and metastasis were evaluated in vitro and in vivo. Data analysis used Kaplan-Meier, Pearson's correlation, and Student t test where appropriate. All statistical tests were two-sided. RESULTS:Here, we report that the patients with high expression of MTHFD2 have a shorter overall survival (HR = 1.62, 95% CI = 1.12 to 2.36, P = .01) and disease-free survival (HR = 1.55, 95% CI = 1.07 to 2.27, P = .02) than patients with low MTHFD2 expression. Suppression of MTHFD2 disturbs NADPH and redox homeostasis and accelerates cell death under oxidative stress, such as hypoxia or anchorage independence (P ≤ .01 for all). Also, genetic or pharmacological inhibition of MTHFD2 suppresses CRC cell growth and lung and peritoneal metastasis in cell-based xenografts (n = 5-8 mice per group). Importantly, LY345899 treatment statistically significantly suppresses tumor growth and decreases the tumor weight in CRC patient-derived xenograft models (n = 10 mice per group, mean [SD] tumor weight of the vehicle-treated group was 1.83 [0.19] mg vs 0.74 [0.30] mg for the LY345899-treated group, P < .001). CONCLUSIONS:Our study presents evidence that MTHFD2 confers redox homeostasis and promotes CRC cell growth and metastasis. The folate analog LY345899 as MTHFD2 inhibitor displays therapeutic activity against CRC and warrants further clinical investigation for CRC treatment. 10.1093/jnci/djy160
METTL3 facilitates tumor progression via an mA-IGF2BP2-dependent mechanism in colorectal carcinoma. Li Ting,Hu Pei-Shan,Zuo Zhixiang,Lin Jin-Fei,Li Xingyang,Wu Qi-Nian,Chen Zhan-Hong,Zeng Zhao-Lei,Wang Feng,Zheng Jian,Chen Demeng,Li Bo,Kang Tie-Bang,Xie Dan,Lin Dongxin,Ju Huai-Qiang,Xu Rui-Hua Molecular cancer BACKGROUND:Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N-methyladenosine (mA) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. METHODS:Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. RESULTS:Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific mA "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including "writer", "reader", and "target", exhibited a better prognostic value for CRC patients than any of these components individually. CONCLUSIONS:Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an mA-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC. 10.1186/s12943-019-1038-7
METTL3 Promotes the Progression of Gastric Cancer via Targeting the MYC Pathway. Yang Dong-Dong,Chen Zhan-Hong,Yu Kai,Lu Jia-Huan,Wu Qi-Nian,Wang Yun,Ju Huai-Qiang,Xu Rui-Hua,Liu Ze-Xian,Zeng Zhao-Lei Frontiers in oncology Methyltransferase-like 3 (METTL3), a major component of the N6-methyladenosine (m6A) methyltransferase complex, has been suggested to function as an oncogene in several cancers. However, its biological mechanism and the involved pathways in gastric cancer (GC) remain unknown. Here, we reported that frequent upregulation of METTL3 was responsible for the aberrant m6A levels in gastric carcinoma. On the other hand, a high level of METTL3 was significantly associated with several clinicopathological features and poor survival in patients with GC. The knockdown of METTL3 effectively inhibited cell proliferation and migration and invasion capacity. Moreover, overexpression of METTL3 considerably augmented its oncogenic function. Integrated RNA-seq and m6A-seq analysis first indicated that several component molecules (e.g., MCM5, MCM6, etc.) of MYC target genes were mediated by METTL3 via altered m6A modification. Our work uncovers the oncogenic roles of METTL3 in GC and suggests a critical mechanism of GC progression. 10.3389/fonc.2020.00115
Correction: ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis. Lu Yun-Xin,Ju Huai-Qiang,Liu Ze-Xian,Chen Dong-Liang,Wang Yun,Zhao Qi,Wu Qi-Nian,Zeng Zhao-Lei,Qiu Hai-Bo,Hu Pei-Shan,Wang Zhi-Qiang,Zhang Dong-Sheng,Wang Feng,Xu Rui-Hua Cancer research 10.1158/0008-5472.CAN-19-1611
A circRNA signature predicts postoperative recurrence in stage II/III colon cancer. Ju Huai-Qiang,Zhao Qi,Wang Feng,Lan Ping,Wang Zixian,Zuo Zhi-Xiang,Wu Qi-Nian,Fan Xin-Juan,Mo Hai-Yu,Chen Li,Li Ting,Ren Chao,Wan Xiang-Bo,Chen Gong,Li Yu-Hong,Jia Wei-Hua,Xu Rui-Hua EMBO molecular medicine Accurate risk stratification for patients with stage II/III colon cancer is pivotal for postoperative treatment decisions. Here, we aimed to identify and validate a circRNA-based signature that could improve postoperative prognostic stratification for these patients. In current retrospective analysis, we included 667 patients with R0 resected stage II/III colon cancer. Using RNA-seq analysis of 20 paired frozen tissues collected postoperation, we profiled differential circRNA expression between patients with and without recurrence, followed by quantitative validation. With clinical information, we generated a four-circRNA-based cirScore to classify patients into high-risk and low-risk groups in the training cohort. The patients with high cirScores in the training cohort had a shorter disease-free survival (DFS) and overall survival (OS) than patients with low cirScores. The prognostic capacity of the classifier was validated in the internal and external cohorts. Loss-of-function assays indicated that the selected circRNAs played functional roles in colon cancer progression. Overall, our four-circRNA-based classifier is a reliable prognostic tool for postoperative disease recurrence in patients with stage II/III colon cancer. 10.15252/emmm.201810168
LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Wang Yun,Lu Jia-Huan,Wu Qi-Nian,Jin Ying,Wang De-Shen,Chen Yan-Xing,Liu Jia,Luo Xiao-Jing,Meng Qi,Pu Heng-Ying,Wang Ying-Nan,Hu Pei-Shan,Liu Ze-Xian,Zeng Zhao-Lei,Zhao Qi,Deng Rong,Zhu Xiao-Feng,Ju Huai-Qiang,Xu Rui-Hua Molecular cancer BACKGROUND:Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. METHODS:We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. RESULTS:LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N-methyladenosine (mA) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. CONCLUSION:LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target. 10.1186/s12943-019-1105-0
Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells. Miao Lei,Qi Jingjing,Zhao Qi,Wu Qi-Nian,Wei Da-Liang,Wei Xiao-Li,Liu Jia,Chen Jun,Zeng Zhao-Lei,Ju Huai-Qiang,Luo Hui-Yan,Xu Rui-Hua Theranostics STING is a critical player in the innate and adaptive immune system, sensing cytosolic DNA to activate the expression of interferon genes and regulate T lymphocytes, which drives immunogenic responses to cancer cells. Tumor-associated macrophages (TAMs), abundantly present in the tumor microenvironment, play a key role in cancer development. Gastric cancer is one of the most common and leading causes in cancer-related death worldwide. However, studies on the function and regulation of STING in TAMs and their roles in gastric cancer progression are still limited. We analyzed STING and CD68 expression of 200 pairs of gastric cancer and adjacent normal tissues by immunohistochemistry to identify the prognostic values of STING, as well as the correlations between STING and CD68 in gastric cancer. The characteristics of STING-altered macrophages, as well as their effects on cancer cell apoptosis and T cell differentiation were examined by flow cytometry. Cytokines secreted by STING-altered macrophages were identified by the Human Inflammation Array3 kit. Concentrations of soluble IL24 and IFN-β were measured by ELISA. models, including spontaneous gastric cancer in p53 mice and cell line-based xenografts, were established, and clinical benefits of STING-altered macrophages were examined. Our study identifies STING as a prognostic factor for gastric cancer, and for the first time demonstrated that knocking-down STING and STING activation by 2'3'-c-GAMP both promote TAMs polarizing into pro-inflammatory subtype and induce apoptosis of gastric cancer cells, mechanistically through IL6R-JAK-IL24 pathway. : This study evaluated effects of targeting STING in TAMs in anti-gastric-cancer therapies. Moreover, we unveil a novel function of STING to activate the IL6R-JAK-IL24 pathway in macrophages. 10.7150/thno.37745
Inhibition of fatty acid catabolism augments the efficacy of oxaliplatin-based chemotherapy in gastrointestinal cancers. Wang Yun,Lu Jia-Huan,Wang Feng,Wang Ying-Nan,He Ming-Ming,Wu Qi-Nian,Lu Yun-Xin,Yu Hong-En,Chen Zhan-Hong,Zhao Qi,Liu Jia,Chen Yan-Xing,Wang De-Shen,Sheng Hui,Liu Ze-Xian,Zeng Zhao-Lei,Xu Rui-Hua,Ju Huai-Qiang Cancer letters Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers. 10.1016/j.canlet.2019.12.036
Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming. Liu Jia,Liu Ze-Xian,Wu Qi-Nian,Lu Yun-Xin,Wong Chau-Wei,Miao Lei,Wang Yun,Wang Zixian,Jin Ying,He Ming-Ming,Ren Chao,Wang De-Shen,Chen Dong-Liang,Pu Heng-Ying,Feng Lin,Li Bo,Xie Dan,Zeng Mu-Sheng,Huang Peng,Lin Aifu,Lin Dongxin,Xu Rui-Hua,Ju Huai-Qiang Nature communications Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target. 10.1038/s41467-020-15112-3
VDR-SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment. Hu Pei-Shan,Li Ting,Lin Jin-Fei,Qiu Miao-Zhen,Wang De-Shen,Liu Ze-Xian,Chen Zhan-Hong,Yang Lu-Ping,Zhang Xiao-Long,Zhao Qi,Chen Yan-Xing,Lu Yun-Xin,Wu Qi-Nian,Pu Heng-Ying,Zeng Zhao-Lei,Xie Dan,Ju Huai-Qiang,Luo Hui-Yan,Xu Rui-Hua Signal transduction and targeted therapy The acidic tumor microenvironment provides an energy source driving malignant tumor progression. Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells. The expression of the vitamin D receptor (VDR) is closely related to the initiation and development of colorectal carcinoma (CRC), but its regulatory mechanism in CRC stem cells is still unclear. Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta (PPARD) expression. Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis. The nuclear export signal in VDR was sensitive to acidosis, and VDR was exported from the nucleus. Chromatin immunoprecipitation (ChIP) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses showed that VDR transcriptionally repressed SRY-box 2 (SOX2) by binding to the vitamin D response elements in the promoter of SOX2, impairing tumor growth and drug resistance. We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo. These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling, resulting in a lack of efficacy of vitamin D in antineoplastic process. 10.1038/s41392-020-00230-7
p.P476S mutation of RBPJL inhibits the efficacy of anti-PD-1 therapy in oesophageal squamous cell carcinoma by blunting T-cell responses. Clinical & translational immunology OBJECTIVES:Anti-PD-1 immune checkpoint blockade represents the onset of a new era in cancer immunotherapy. However, robust predictors are necessary for screening patients with immune checkpoint-responsive oesophageal squamous cell carcinoma (ESCC). METHODS:We obtained biopsy samples from an ESCC patient with mixed responses. The expression of CD4, CD8, CD68, PD-L1, RBPJL and IL-16 was analysed by immunohistochemistry, and the correlation with prognostic value was obtained from the GEPIA portal. T-cell functions were examined by flow cytometry, MTS and transwell assays. The secreted cytokines were identified using an Inflammation Array Kit. The concentration of soluble IFN-γ was measured by enzyme-linked immunosorbent assay. The clinical benefit of RBPJL was examined in a PBMC xenograft mouse model. RESULTS:The patient had an exceptional clinical response with shrinkage of the primary oesophageal and lung metastatic lesions as well as enlargement of liver metastatic lesions after toripalimab monotherapy. Four liver-specific gene mutations were identified. RBPJL showed better response to toripalimab in the PBMC cell-derived xenograft (CDX) ESCC model. Conditional medium from RBPJL overexpression induced chemotaxis and proliferation of T lymphocytes, as well as Th2/Th1 differentiation through the RBPJL-NF-κB-IL-16 axis . These functions were all inhibited by the p.P476S mutation of RBPJL (RBPJL (p.P476S)). CONCLUSIONS:We report for the first time that RBPJL (p.P476S) promotes tumor growth in ESCC and inhibits the efficacy of anti-PD-1 therapy through blunting T-cell responses. Our findings provide a potential new predictor for evaluating the efficacy of anti-PD-1 therapy in ESCC patients. 10.1002/cti2.1172
Systematic analysis of the transcriptome in small-cell carcinoma of the oesophagus reveals its immune microenvironment. Clinical & translational immunology OBJECTIVES:Although the genomic landscape of small-cell carcinoma of the oesophagus (SCCE) has been dissected, its transcriptome-level aberration and immune microenvironment status are unknown. METHODS:Using ultra-deep whole transcriptome sequencing, we analysed the expression profile of nine paired SCCE samples and compared the transcriptome with public transcriptomic data set of normal oesophageal mucosa and other cancer types. Based on the transcriptome data, the immune signatures were investigated. The genomic data of 55 SCCE samples were also applied for immune checkpoint blockade therapy (ICBT) biomarker evaluation including microsatellite instability (MSI) status, tumor mutation burden (TMB) and neoantigen burden (TNB). Also, we evaluated the CD8, CD68 and programmed death-ligand 1 (PD-L1) in 62 retrospective SCCE samples with IHC assay. RESULTS:Differential expression analysis revealed that the cell cycle, p53, and Wnt pathways are significantly deregulated in SCCE. Immune microenvironment analysis showed that high leucocyte infiltration and adaptive immune resistance did occur in certain individuals, while the majority showed a relatively suppressive immune status. Immune checkpoints such as CD276 and LAG-3 were upregulated, and higher M2 macrophage infiltration in tumor tissues. Furthermore, normal tissues adjacent to the tumors of SCCE presented a more activated inflammatory status than tumor-free healthy controls. These observations showed that ICBT might benefit SCCE patients. As the critical biomarker of ICBT, TMB of SCCE was 3.64 with the predictive objective response rate 13.2%, while the PD-L1-positive rate was 43%. CONCLUSIONS:Our study systematically characterized the immune microenvironment in small-cell carcinoma of the esophagus and provided evidence that several patients with SCCE may benefit from immune checkpoint blockade therapy. 10.1002/cti2.1173
MAP kinase-interacting serine/threonine kinase 2 promotes proliferation, metastasis, and predicts poor prognosis in non-small cell lung cancer. Guo Zhihua,Peng Guilin,Li Ermao,Xi Shaoyan,Zhang Yu,Li Yong,Lin Xiaodong,Li Guangqiu,Wu Qinian,He Jianxing Scientific reports We hypothesized that MAP kinase-interacting serine/threonine kinase 2 (MNK2) may contribute to non-small cell lung cancer (NSCLC) development, and serve as a new therapeutic target. Immunohistochemical staining evaluated the correlation between MNK2 expression and clinicopathological features in 367 NSCLC cancer tissues. We determined the effects of MNK2 silencing in NSCLC cell lines in vitro and in vivo. RT-PCR and western blotting was used to examine the impact of MNK2 on ERK and AKT pathways. MNK2 was overexpressed in NSCLC cell lines and tumor tissues. Patients with MNK2 overexpression had lower OS rates (P < 0.001). High expression of MNK2 was correlated with lymph node metastasis (P = 0.008). MNK2 functioned as an independent prognostic factor for poor survival in patients with NSCLC (P = 0.003). MNK2 down-regulation inhibited proliferation, migration and invasion in vitro (P < 0.001), and reduced tumor growth and invasion in nude mice (P < 0.05). MNK2 enhanced phosphorylation of eIF4E, a downstream target of ERK and AKT pathways, which promoted NSCLC proliferation and invasion. We conclude that MNK2 overexpression in NSCLC is associated with proliferation, migration, invasion, and lower survival rates in patients via the phosphorylated eIF4E-mediated signaling pathway. 10.1038/s41598-017-10397-9
Serum EBV EA-IgA and VCA-IgA antibodies can be used for risk group stratification and prognostic prediction in extranodal NK/T cell lymphoma: 24-year experience at a single institution. Huang Yuhua,Rao Huilan,Yan Shumei,Wang Fang,Wu Qinian,Feng Yanfen,Zhang Yujing Annals of hematology Although extranodal NK/T cell lymphoma (ENKTCL) is consistently associated with Epstein-Barr virus (EBV) infection, the manifestation and prognostic value of serum EBV antibodies still remain unknown. One hundred and forty-one patients with ENKTCL were evaluated for serum EBV EA-IgA and VCA-IgA antibodies levels in the past 24 years in our institution. Their correlation with clinicopathological features, plasma EBV DNA load, and patients' outcomes was analyzed. EBV EA-IgA ≥1:10 and VCA-IgA ≥1:160 were found in 18.4 and 16.3% of patients, respectively. They correlated with adverse ENKTCL profile and inferior overall survival (OS) and progression-free survival (PFS). EA-IgA ≥1:10 was an independent prognostic factor on OS (RR = 2.276, p = 0.008) and associated with lower complete response (CR) rate (34.8 vs 70.6%, p = 0.001) and higher relapse rate in CR patients (62.5 vs 34.7%, p = 0.016). In subgroup analysis, both EA-IgA ≥1:10 and VCA-IgA ≥1:160 significantly correlated with inferior OS and PFS in patients with stage I/II, IPI score 0-1, plasma EBV DNA (+), and CR. Patients with plasma EBV DNA (+) and EA-IgA ≥1:10 (or VCA-IgA ≥1:160) had significantly shorter periods of OS and PFS in comparison with other corresponding groups. Elevated serum EBV EA-IgA and VCA-IgA levels were related to adverse ENKTCL profile and correlated with poor treatment response, early relapse, and poor prognosis in patients with ENKTCL. These findings provide convincing evidence for the use of serum EBV EA-IgA and VCA-IgA antibodies for risk group stratification and prognostic prediction in ENKTCL. 10.1007/s00277-017-3013-y