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    Long Noncoding RNA AFAP1-AS1 Promotes Cell Proliferation and Apoptosis of Gastric Cancer Cells via PTEN/p-AKT Pathway. Guo Jun-Qiang,Li Shi-Jie,Guo Guo-Xiao Digestive diseases and sciences BACKGROUND:Long noncoding RNA (lncRNA) plays critical roles in both tumor-suppressive and oncogenic pathways in the pathological development and prognosis of cancers. AIMS:This study aimed to explore the expression of lncRNA AFAP1-AS1 and its function in gastric cancer (GC). METHODS:The expression of AFAP1-AS1 was detected in GC tissues and GC cells by quantitative real-time reverse-transcription PCR. A small interfering RNA (siRNA) that targeted AFAP1-AS1 was transfected into cells to inhibit the expression of AFAP1-AS1. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and colony formation assay were performed to examine the cell proliferation of SGC7901 cell transfected with si-AFAP1-AS1. Cell apoptosis was detected by flow cytometry. The protein level of cleaved PARP, Caspase 3, Caspase 9, Caspase 8, Bcl-2, Bax, p-AKT, total-AKT, and PTEN were detected by Western blot. RESULTS:AFAP1-AS1 was up-regulated in GC tissues and GC cells. AFAP1-AS1 knockdown suppressed cell viability of SGC7901 transfected with si-AFAP1-AS1. The number of apoptotic SGC7901 cell transfected with si-AFAP1-AS1 was increased by 3.4-fold comparing to that of control. The protein level of cleaved PARP, Caspase 3, and Caspase 9 were increased in SGC7901 transfected with si-AFAP1-AS1, as well as the expression of Bax. The protein level of Bcl-2 was decreased. AFAP1-AS1 knockdown decreased the protein level of p-AKT and increased the expression of PTEN in SGC7901 cells. CONCLUSIONS:AFAP1-AS1 was up-regulated in GC cells and regulated the gastric cancer cell proliferation and apoptosis via PTEN/p-AKT pathway. 10.1007/s10620-017-4584-0
    miR-638 suppresses cell proliferation in gastric cancer by targeting Sp2. Zhao Ling Yu,Yao Yu,Han Jia,Yang Juan,Wang Xiao Fei,Tong Dong Dong,Song Tu Sheng,Huang Chen,Shao Yuan Digestive diseases and sciences BACKGROUND:MicroRNAs play important roles in the development and progression of various cancers. Recent studies have shown that miR-638 was downregulated in several tumors; however, its role in gastric cancer (GC) has not been investigated in detail. AIMS:The purpose of this study was to determine the role of miR-638 and to elucidate its regulatory mechanism in GC. METHODS:The expression levels of miR-638 and specificity protein 2 (Sp2) were detected by real-time PCR and Western blotting in GC. After pcDNA6.2-GW/EmGFP-miR-638 vector, miR-638 inhibitor and Sp2-siRNA transfection, the AGS cell proliferation was investigated by MTT assay and cell cycle, and apoptosis was detected using the Annexin V/PI. In addition, the regulation of Sp2 by miR-638 was evaluated by real-time RT-PCR, Western blot and luciferase reporter assays; cyclin D1 expression was measured by Western blotting. RESULTS:The expression of miR-638 is dramatically down-regulated and Sp2 expression is remarkably up-regulated in GC tissues. Luciferase assays revealed that miR-638 inhibited Sp2 expression by targeting the 3'-UTR of Sp2 mRNA. Overexpression of miR-638 and Sp2-siRNA reduced Sp2 expression at both the mRNA and protein levels in vitro, and inhibition of miR-638 increased Sp2 expression. Moreover, we found that miR-638 overexpression and Sp2-siRNA markedly suppressed cell proliferation with decreasing expression of cyclin D1 and inducing G1-phase cell-cycle arrest in vitro; inhibition of miR-638 significantly promoted cell proliferation by increasing expression of cyclin D1 and leading more cells into the S and G2/M phase. CONCLUSIONS:Our results demonstrated that miR-638 suppressed GC cell proliferation by targeting Sp2 with influence on the expression of cyclin D1. We suggest that miR-638 might be a candidate predictor or an anticancer therapeutic target for GC patients. 10.1007/s10620-014-3087-5
    Combined exercise ameliorates ovariectomy-induced cognitive impairment by enhancing cell proliferation and suppressing apoptosis. Kim Tae-Woon,Kim Chang-Sun,Kim Ji-Yeon,Kim Chang-Ju,Seo Jin-Hee Menopause (New York, N.Y.) OBJECTIVE:Estrogen plays an important role in cognitive function, including attention, learning, and memory, and affects the structure and function of brain areas. We investigated the effects of combined exercise on memory deficits induced by ovariectomy (OVX) in relation to cell proliferation and apoptosis in the hippocampus. METHODS:Rats were randomly divided into four groups: sham, sham and exercise, OVX, and OVX and exercise. Rats in combined exercise groups were subjected to 3 days of resistance training and 3 days of running (for a total of 6 d/wk) for eight consecutive weeks. Rats were tested in step-down avoidance task and Morris water maze task to verify the effects of OVX on short-term and spatial working memory. RESULTS:In the present study, the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor, TrkB, and Bcl-2 decreased; expression of Bax and the number of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells increased; and short-term and spatial working memory decreased in the OVX group compared with the sham group. Conversely, when the combined exercise group was compared with the OVX group, the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor, TrkB, and Bcl-2 increased; expression of Bax and the number of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells decreased; and short-term and spatial working memory increased. CONCLUSIONS:Combined exercise increases cell proliferation and inhibits apoptosis in the hippocampus and improves cognitive function despite estrogen deficiency. 10.1097/GME.0000000000000486
    miR-146b Regulates Cell Proliferation and Apoptosis in Gastric Cancer by Targeting PTP1B. Xu Jianguo,Zhang Zilong,Chen Qing,Yang Lin,Yin Jiao Digestive diseases and sciences BACKGROUND/AIMS:The purpose of this study is to explore the inhibition or activation effects of microRNA-146 B on the expression of PTP1B in gastric cancer cells. METHODS:The expressions of PTP1B and miR-146b in gastric cancer were detected by RT-qPCR. The effects of miR-146b on cell apoptosis and proliferation of gastric cancer were detected. The methods used in the detection process included Annexin V/PI dying method, colony formation assay, and MTT assay. The downstream target gene miR-146b was predicted and screened by bioinformatics and luciferase reporter assay. The mRNA and protein expressions of the target gene PTP1B miR-146b were determined using RT-qPCR and western blot. The expression of miR-146 B in mice was detected by the cells transfected with microRNA-146 B in vivo. RESULTS:Compared with normal tissues, PTP1B was higher and miR-146b was lower in cancer cells. Over-expression of miR-146b can inhibit cell viability and increase the apoptosis rate. According to the luciferase reporter assay, PTP1B was the downstream target gene of miR-146b. The re-introduction of PTP1B reversed the growth inhibition and apoptosis of gastric cancer cells induced by miR-146b. From the mouse xenograft model, the over-expression of miR-146b inhibited the tumor growth and reduced the expression level of PTP1B. CONCLUSION:miR-146b directly inhibits the expression of PTP1B and suppressed the growth and development of gastric cancer. 10.1007/s10620-019-05771-8
    SNHG10 Promotes Cell Proliferation and Migration in Gastric Cancer by Targeting miR-495-3p/CTNNB1 Axis. Yuan Xiu,Yang Tianwen,Xu Yun,Ou Shan,Shi Peng,Cao Ming,Zuo Xin,Liu Qinglan,Yao Jie Digestive diseases and sciences BACKGROUND:Long non-coding RNAs have been acknowledged as the crucial regulators in the progression of human cancers, including gastric cancer (GC). Small nucleolar RNA host gene 10 (SNHG10) has been identified as an oncogene in several cancer types. Nonetheless, it is unclear whether SNHG10 exerts functions in GC cells. AIMS:The aims of the current study were to explore the function and underlying mechanism of SNHG10 in GC. METHODS:The expression levels of SNHG10, miR-495-3p and catenin beta 1 (CTNNB1) were detected by RT-qPCR. Loss-of-function assays, including CCK-8, colony formation assay, flow cytometry analysis and transwell assays, were conducted to verify the effect of SHNG10 on the proliferation, apoptosis, migration and invasion of GC cells. Mechanism experiments were performed to identify the downstream molecular mechanism of SNHG10. RESULTS:SNHG10 was expressed at a high level in GC cells. Knockdown of SNHG10 inhibited the proliferation, migration and invasion of GC cells. Silencing of SNHG10 led to the downregulation of core factors of WNT signaling pathway. Knockdown of SNHG10 could decline the expression of CTNNB1 through sequestering miR-495-3p. CONCLUSIONS:SNHG10 promotes the procession of GC through targeting miR-495-3p/CTNNB1 and activating WNT signaling pathway. 10.1007/s10620-020-06576-w
    TCF19 Promotes Cell Proliferation through Binding to the Histone H3K4me3 Mark. Mondal Payel,Sen Sabyasachi,Klein Brianna J,Tiwary Niharika,Gadad Shrikanth S,Kutateladze Tatiana G,Roy Siddhartha,Das Chandrima Biochemistry Transcription factor 19 (TCF19) plays critical roles in type 1 diabetes and the maintenance of pancreatic β cells. Recent studies have also implicated TCF19 in cell proliferation of hepatic carcinoma and non-small cell lung carcinoma; however, the mechanism underlying this regulation remains elusive. At the molecular level, TCF19 contains two modules, the plant homeodomain (PHD) finger and the forkhead-associated (FHA) domain, of unclear function. Here, we show that TCF19 mediates hepatocellular carcinoma HepG2 cell proliferation through its PHD finger that recognizes trimethylated lysine 4 of histone 3 (H3K4me3). W316 of the PHD finger of TCF19 is one of the critical residues eliciting this function. Whole genome microarray analysis and orthogonal cell-based assays identified a large subset of genes involved in cell survival and proliferation that depend on TCF19. Our data suggest that TCF19 acts as a pro-oncogene in hepatocellular carcinoma cells and that its functional PHD finger is critical in cell proliferation. 10.1021/acs.biochem.9b00771
    LncRNA E2F-Mediated Cell Proliferation Enhancing lncRNA Regulates Cancer Cell Behaviors and Affects Prognosis of Gastric Cancer. Fu Jing,Zhao Wenxing,Guo Dongmei,Li Zheng Digestive diseases and sciences BACKGROUND:A recent study reported a novel long non-coding RNA (lncRNA) E2F-mediated cell proliferation enhancing lncRNA (EPEL, human chromosome 4, intergenic region) plays an oncogenic role in lung cancer. AIMS:We aimed to investigate the role of lncRNA EPEL in gastric cancer. METHODS:Gene expression was analyzed by RT-qPCR and western blot. Survival analysis was performed by comparing survival curves. Cell proliferation, migration, and invasion were analyzed by CCK-8 and Transwell assays. RESULTS:We found that lncRNA EPEL and Runt-related transcription factor 2 (RUNX2) were both upregulated in gastric cancer. EPEL and RUNX2 were positively correlated in tumor. Patients with high expression level of lncRNA EPEL showed poor survival. LncRNA EPEL and RUNX2 overexpression promoted, while lncRNA EPEL siRNA silencing inhibited the migration, proliferation, and invasion of gastric cancers. In addition, RUNX2 overexpression completely rescued the inhibited cancer cell migration, proliferation, and invasion caused by lncRNA EPEL siRNA silencing. Consistently, EPEL overexpression resulted in upregulated RUNX2 expression, while RUNX2 overexpression did not affect lncRNA EPEL expression. CONCLUSIONS:Therefore, lncRNA EPEL may regulate cancer cell behaviors and affect prognosis of gastric cancer by interacting with RUNX2. 10.1007/s10620-019-05855-5
    MiR-3150b inhibits hepatocellular carcinoma cell proliferation, migration and invasion by targeting GOLPH3. Zhang Yi,Wang Jianjun,Su Hongling Journal of investigative medicine : the official publication of the American Federation for Clinical Research BACKGROUND:In this study, we aimed to explore the potential involvement of miR-3150b in hepatocellular carcinoma (HCC) carcinogenesis. METHODS:The expression of miR-3150b and Golgi phosphoprotein 3 (GOLPH3) was determined in HCC cell lines. Cell proliferation, migration and invasion were estimated by Cell Counting Kit-8, wound healing and Transwell assays. The association between miR-3150b and GOLPH3 was verified by luciferase assay. RESULTS:MiR-3150b was downregulated, while GOLPH3 was remarkably upregulated in HCC cells. Furthermore, miR-3150b inhibited HCC cell proliferation, migration and invasion. MiR-3150b directly targeted and negatively regulated GOLPH3. CONCLUSION:MiR-3150b suppressed HCC cell proliferation, invasion and migration by targeting GOLPH3. 10.1136/jim-2019-001181
    Circular RNA PTK2 Accelerates Cell Proliferation and Inhibits Cell Apoptosis in Gastric Carcinoma via miR-139-3p. Yu Deliang,Zhang Chi Digestive diseases and sciences BACKGROUND:Gastric carcinoma (GC) is one of the most common malignant tumors. Although increasing studies have indicated that circular RNAs function as ideal biomarkers for multiple cancers, only a few researches elucidated the correlation between circular RNA PTK2 (circPTK2) and human cancers. AIM:To further explore the expression status, biological function, and regulatory mechanism of circPTK2 in GC. METHODS:Bioinformatics analysis and function or mechanism experiments including RT-qPCR, flow cytometry, Western blot, luciferase reporter assay, and xenografts assays were applied to investigate the function of circPTK2 and miR-139-3p. RESULTS:High expression of circPTK2 was presented in GC tissues and cells. The circPTK2 knockdown notably suppressed cell proliferation and promoted cell apoptosis in GC. In mechanism, circPTK2 served as a sponge of miR-139-3p. Inhibition of miR-139-3p could reverse circPTK2 silence-mediated effects on GC cell proliferation and apoptosis. Furthermore, the xenograft tumor model was established to investigate the role of circPTK2 in GC tumor growth. Experimental results delineated that the reduction in tumor growth in response to circPTK2 knockdown was partly recovered by miR-139-3p inhibitor. CONCLUSIONS:CircPTK2 promotes GC development by sponging miR-139-3p, which may function as an effective gene target for managing GC. 10.1007/s10620-020-06358-4
    Knockdown Inhibits Cell Proliferation and Cell Apoptosis, and Is Negatively Regulated by miR-4779 in Osteosarcoma Cells. Zhu Jiajun,Cui Kai,Cui Yan,Ma Chengbin,Zhang Zhiyu DNA and cell biology Polo-like kinase 1 (PLK1) is a ubiquitous serine/threonine protein kinase. It is reported to be involved in the occurrence and progression of various human cancers. In the present study, we explored the role and molecular mechanism of in the proliferation of osteosarcoma (OS) cells. We found that expression was higher in MG63/Dox cells than in MG63 cells, while inhibiting or interfering with the level of suppressed cell proliferation of MG63/Dox cells. TargetScan analysis predicted that miR-4779 would interact with the 3'-UTR of PLK1 mRNAs and also inhibit cell autophagy of MG63/Dox cells. The data demonstrated that miR-4779 negatively regulates the expression of , and both miR-4779 and regulate cell proliferation and cell apoptosis of MG63/Dox cells, processes that are involved in the drug resistance of OS cells. 10.1089/dna.2019.5002
    miRNA-106a Promotes Breast Cancer Cell Proliferation, Clonogenicity, Migration, and Invasion Through Inhibiting Apoptosis and Chemosensitivity. You Faping,Luan Hong,Sun Dan,Cui Tao,Ding Pengpeng,Tang Haitao,Sun Diwen DNA and cell biology To explore the effect of miR-106a in breast cancer cell behavior and sensitivity to chemotherapeutic agents. Tumor tissue and adjacent normal tissue were derived from 40 breast cancer patients, and miR-106a expression was measured by reverse transcription-qPCR. Breast cancer cells, MDA-MB-231 and MCF-7, were treated with miRNA-106a mimic (MM) or miRNA-106a inhibitor (MI) and negative controls. Cell proliferation was measured by MTT assay. Clonogenicity was measured by colony-forming assay. Cell migration and invasion ability were measured by scratch test and transwell assay, respectively. Apoptosis was determined by flow cytometry, and chemosensitivity to cisplatin was measured by MTT assay. Finally, protein expression of p53, Bax, Bcl-2, RUNX3, and ABCG2 was quantified by western blot. miR-106a expression was significantly upregulated in human breast cancer tissue relative to adjacent normal tissue. Upregulation of miR-106a enhanced breast cancer cell proliferation, colony-forming capacity, migration, and invasion of cultured breast cancer cells. Additionally, miR-106a overexpression significantly decreased breast cancer cell apoptosis and sensitivity to cisplatin. Finally, we showed miR-106a overexpression upregulated the levels of Bcl-2 and ABCG2, and downregulated the expression of P53, Bax, and RUNX3. miR-106a promotes breast cancer cell proliferation and invasion through upregulation of Bcl-2, ABCG2, and P53, and downregulation of Bax and RUNX3. 10.1089/dna.2018.4282
    Long Non-coding RNA LINC01503 Promotes Gastric Cancer Cell Proliferation and Invasion by Regulating Wnt Signaling. Ding Jian,Shi Feng,Xie Guangdong,Zhu Yong Digestive diseases and sciences BACKGROUND:Previous studies have indicated that the dysregulation of long non-coding RNAs plays an important role in tumors. LINC01503 is a newly discovered lncRNA that promotes development of various tumor types. However, the function of LINC01503 in gastric cancer has not been reported yet. AIMS:To explore the function of LINC01503 in gastric cancer development and the underlying molecular biological regulatory mechanisms. METHODS:LINC01503 expression in tissues and cell lines of gastric cancer were determined through qRT-PCR. Transwell assay and cell number counting experiments were employed to detect the cell invasion and proliferation. C-myc, cyclin D1, and β-catenin expressions were analyzed through Western blot and qRT-PCR. RESULTS:LINC01503 was highly expressed in gastric cancer tissues and cell lines, which was correlated with poor prognosis. Knockdown of LINC01503 suppressed gastric cancer cell proliferation and invasion, whereas overexpression of LINC01503 showed a reverse trend. Silencing LINC01503 significantly inhibited the expression of c-myc, cyclin D1, and β-catenin. Overexpressing β-catenin rescued the inhibitory effects, induced by LINC01503 silencing, on gastric cancer cell proliferation and metastasis. CONCLUSIONS:This research reported that the elevated expression of LINC01503 could promote proliferation and metastasis of gastric cancer through positively regulating the Wnt/β-catenin pathway. 10.1007/s10620-020-06215-4
    Caused DNA Damage and Promoted Cell Proliferation by the / Pathway in Oral Cancer Cells. Geng Fengxue,Zhang Yunjia,Lu Ze,Zhang Shuwei,Pan Yaping DNA and cell biology Bacterial infection influences genomic stability and integrity by causing DNA damage, which increases the possibility of tumor initiation and development. We aimed to investigate whether , one of the periodontal pathogens, promoted oral squamous cell carcinoma (OSCC) by causing DNA double-strand break (DSB). Tca8113 tongue squamous cell carcinoma cells were infected with . The expression of γH2AX was detected by western blots and immunofluorescence. The proliferation and cell cycle alterations were tested by CCK8 and flow cytometry, respectively. The expression levels of Ku70, p53, and p27 were evaluated by quantitative real-time polymerase chain reaction and western blots. A plasmid was used for the overexpression of Ku70 to verify the possible relationship between Ku70 and p53. We confirmed the presence of DSBs in the response to by detecting the expression of γH2AX. The cell proliferation ability was increased with an accelerated cell cycle while the expression of p27 was decreased. Meanwhile, the expression of Ku70 and wild p53 was downregulated. When Ku70 was overexpressed, the expression of wild p53 in response to infection was upregulated and cell proliferation was accordingly inhibited. We concluded that infection promoted the proliferation ability of Tca8113 by causing DNA damage via the Ku70/p53 pathway. 10.1089/dna.2019.5064
    miR-4326 promotes lung cancer cell proliferation through targeting tumor suppressor APC2. Xu Guopeng,Zhang Zhongwei,Zhang Li,Chen Ying,Li Ning,Lv Yantian,Li Yong,Xu Xiao Molecular and cellular biochemistry microRNAs have been reported to play vital role in lung cancer proliferation and metastasis; the role of miR-4326 in tumor progression has not been studied. Here, we studied the effect of miR-4326 on lung cancer cell proliferation; we found that miR-4326 was significantly upregulated in lung cancer tissues determined using TCGA dataset and clinical specimens, meanwhile it was also upregulated in lung cancer cells. Overexpression of miR-4326 promoted lung cancer cell proliferation analyzed by MTT, soft agar growth, and BrdU incorporation assay, while miR-4326 knockdown suppressed lung cancer cell proliferation. We found miR-4326 targets tumor suppressor adenomatous polyposis coli 2 (APC2), which is a negative regulator of Wnt pathway, by binding to the 3'UTR of APC2. Wnt pathway could increase Cyclin D1 and c-MYC expression, we also found that miR-4326 could increase their expression, suggesting that APC2 was the target of miR-4326. Moreover, double knockdown of APC2 and miR-4326 promoted lung cancer cell proliferation, confirming that miR-4326 promoted lung cancer cell proliferation by inhibiting APC2. 10.1007/s11010-017-3219-2
    Kin17 facilitates thyroid cancer cell proliferation, migration, and invasion by activating p38 MAPK signaling pathway. Jiang Qun-Guang,Xiong Cheng-Feng,Lv Yun-Xia Molecular and cellular biochemistry Kin17 DNA and RNA binding protein (Kin17) is an extremely conserved nuclear protein that is almost expressed in every type of mammal cells. Recently, Kin17 has been implicated into the regulation of tumorigenesis of diverse human cancers. However, its functions in thyroid cancer (TC) are still largely unexplored. Kin17 mRNA and protein level were tested by qRT-PCR and western blot, respectively. Effects of Kin17 on TC cell proliferation were estimated by colony formation assay and flow cytometry analysis in vitro as well as by in vivo tumor growth experiment. TC cell migratory and invasive capacities were assessed via wound-healing and transwell experiments. Epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin and N-cadherin) and p38 MAPAK signaling pathway-related proteins (p-p38, p38, Cyclin D1, and p27) were examined via western blot. Kin17 was remarkably increased in TC tissue samples and cell lines at both mRNA and protein levels compared to normal tissue and control cell line. Knockdown of Kin17 obviously repressed TC cell proliferation, arrested cell cycle, and inhibited TC cell migration and invasion in vitro, while overexpression of Kin17 produced opposite effects. Kin17 knockdown suppressed p38 MAPK signaling pathway, while Kin17 overexpression activated this pathway. Treatment of p38 agonist (p79350) abolished the repressive effects of sh-Kin17 on TC cell proliferation, migration, and invasion, as well as on p38 pathway. Kin17 knockdown was also found to enhance the sensitivity of Doxorubicin of TC cells. In addition, Kin17 knockdown in vivo also markedly repressed TC tumor growth and p38 pathway. Kin17 functioned as an oncogene of TC by activating p38 MAPK signaling pathway. 10.1007/s11010-020-03939-9
    A role for Hippo/YAP-signaling in FGF-induced lens epithelial cell proliferation and fibre differentiation. Dawes L J,Shelley E J,McAvoy J W,Lovicu F J Experimental eye research Recent studies indicate an important role for the transcriptional co-activator Yes-associated protein (YAP), and its regulatory pathway Hippo, in controlling cell growth and fate during lens development; however, the exogenous factors that promote this pathway are yet to be identified. Given that fibroblast growth factor (FGF)-signaling is an established regulator of lens cell behavior, the current study investigates the relationship between this pathway and Hippo/YAP-signaling during lens cell proliferation and fibre differentiation. Rat lens epithelial explants were cultured with FGF2 to induce epithelial cell proliferation or fibre differentiation. Immunolabeling methods were used to detect the expression of Hippo-signaling components, Total and Phosphorylated YAP, as well as fibre cell markers, Prox-1 and β-crystallin. FGF-induced lens cell proliferation was associated with a strong nuclear localisation of Total-YAP and low-level immuno-staining for phosphorylated-YAP. FGF-induced lens fibre differentiation was associated with a significant increase in cytoplasmic phosphorylated YAP (inactive state) and enhanced expression of core Hippo-signaling components. Inhibition of YAP with Verteporfin suppressed FGF-induced lens cell proliferation and ablated cell elongation during lens fibre differentiation. Inhibition of either FGFR- or MEK/ERK-signaling suppressed FGF-promoted YAP nuclear translocation. Here we propose that FGF promotes Hippo/YAP-signaling during lens cell proliferation and differentiation, with FGF-induced nuclear-YAP expression playing an essential role in promoting the proliferation of lens epithelial cells. An FGF-induced switch from proliferation to differentiation, hence regulation of lens growth, may play a key role in mediating Hippo suppression of YAP transcriptional activity. 10.1016/j.exer.2018.01.014
    The circular RNA circSlc7a11 promotes bone cancer pain pathogenesis in rats by modulating LLC-WRC 256 cell proliferation and apoptosis. Chen Han-Wen,Zhang Xiao-Xia,Peng Zhu-Ding,Xing Zu-Min,Zhang Yi-Wen,Li Ya-Lan Molecular and cellular biochemistry Treatment of bone cancer pain (BCP) caused by bone metastasis in advanced cancers remains a challenge in clinical oncology, and the underlying mechanisms of BCP are poorly understood. This study aimed to investigate the pathogenic roles of circular RNAs (circRNAs) in regulating cancer cell proliferation and BCP development. Eight differentially expressed circRNAs in the rat spinal cord were validated by agarose gel electrophoresis and Sanger sequencing. Expression of circRNAs and mRNAs was detected by quantitative RT-PCR. MTS assay and flow cytometry were performed to analyze cell proliferation and apoptosis, respectively. Differentially expressed mRNA profiles were characterized by deep RNA sequencing, hierarchical clustering, and functional categorization. The interactions among circRNAs, microRNAs (miRNAs), and mRNAs were predicted using TargetScan. Additionally, western blot was performed to determine the protein levels of Pax8, Isg15, and Cxcl10. Multiple circRNAs were differentially expressed in the spinal cords of BCP model rats; of these, circSlc7a11 showed the greatest increase in expression. The overexpression of circSlc7a11 significantly promoted cell proliferation and repressed apoptosis of LLC-WRC 256 and UMR-106 cells, whereas circSlc7a11 silencing produced the opposite effects. Altered expression of circSlc7a11 also induced substantial changes in the mRNA expression profiles of LLC-WRC 256 cells; these changes were linked to multiple apoptotic processes and signaling pathways, such as the chemokine signaling pathway, and formed a complex circRNA/miRNA/mRNA network. Additionally, Pax8, Isg15, and Cxc110 protein level in LLC-WRC 256 cells was consistent with the mRNA results. The circRNA circSlc7a11 regulates rat BCP development by modulating LLC-WRC 256 cell proliferation and apoptosis through multiple-signaling mechanisms. 10.1007/s11010-020-04020-1
    Dual roles of TGF-β signaling in the regulation of dental epithelial cell proliferation. Zhang Hao,Zhan Yunyan,Zhang Yue,Yuan Guohua,Yang Guobin Journal of molecular histology The purpose of this study is to investigate the molecular mechanisms and biological function of TGF-β-activated Smad1/5 in dental epithelium. Immunohistochemistry was used to detect the expressions of TGF-β signaling-related gene in mice molar germ. Primary dental epithelial cells were cultured and treated with TGF-β1 at a concentration of 0.5 or 5 ng/mL. Small molecular inhibitors, SB431542 and ML347, was used to inhibite ALK5 and ALK1/2, respectively. Small interfering RNA was used to knock down Smad1/5 or Smad2/3. The proliferation rate of cells was evaluated by EdU assay. In the basal layer of dental epithelial bud TGF-β1 and p-Smad1/5 were highly expressed, and in the interior of the epithelial bud TGF-β1 was lowly expressed, whereas p-Smad2/3 was highly expressed. In primary cultured dental epithelial cells, low concentration of TGF-β1 activated Smad2/3 but not Smad1/5, while high concentration of TGF-β1 was able to activate both Smad2/3 and Smad1/5. SB431542 but not ML347 was able to block the phosphorylation of Smad2/3 by TGF-β1. Either SB431542 or ML347 was able to block the phosphorylation of Smad1/5 by TGF-β1. EdU staining showed that high concentration of TGF-β1 promoted dental epithelial cell proliferation, which was reversed by silencing Smad1/5, whereas low concentration of TGF-β1 inhibited cell proliferation, which was reversed by silencing Smad2/3. In conclusions, TGF-β exhibits dual roles in the regulation of dental epithelial cell proliferation through two pathways. On the one hand, TGF-β activates canonical Smad2/3 signaling through ALK5, inhibiting the proliferation of internal dental epithelial cells. On the other hand, TGF-β activates noncanonical Smad1/5 signaling through ALK1/2-ALK5, promoting the proliferation of basal cells in the dental epithelial bud. 10.1007/s10735-020-09925-1
    CD8 Treg Cells Inhibit B-Cell Proliferation and Immunoglobulin Production. Gupta Sudhir,Su Houfen,Agrawal Sudhanshu International archives of allergy and immunology AIM:The role of CD4+ Treg in immune responses has been well established. More recently, a role of CD8+ T regulatory cells (CD8 Treg) in the regulation of immune responses in health and autoimmune diseases has been investigated. Furthermore, different investigators have used different markers to define CD8 Treg. Finally, regulatory effects of CD8 Treg have been studied against T-cell responses; however, their role in regulating B-cell proliferation and immunoglobulin production has not been evaluated. Therefore, in this study we examined the effect of two types of CD8 Treg on B-cell proliferation and immunoglobulin production. METHODS:Purified CD8+ T cells were activated with anti-CD3/CD28 for 48 h and then sorted into two different types of CD8 Treg as defined by two different sets of markers, CD8+CD183+CD197+CD45RA- and CD8+CD183+CD25highCD278+. Purified B cells were cocultured with sorted CD8 Treg at 1:1, 1:1/2, and 1:1/4 ratios and activated with anti-CD40 and CpG. B-cell proliferation was assessed by the CFSE dye dilution assay and immunoglobulin production by the ELISA assay. RESULTS:Our data show CD183+CD197+CD45RA-CD8 Treg significantly inhibited B-cell proliferation and inhibited IgM and IgG production but not IgA production at 1:1 ratio only. However, CD183+CD25highCD278+CD8 Treg inhibited significantly B-cell proliferation at 1:1 and 1:1/2 ratios and IgM, IgG, and IgA production at all ratios. CONCLUSION:CD8 Treg regulate B-cell responses, and CD183+CD25highCD278+CD8 Treg are more powerful regulators of B-cell proliferation and immunoglobulin production than CD183+CD197+CD45RA-CD8 Treg and, therefore, may be used as preferred markers for CD8 Treg. 10.1159/000509607
    Knockdown of Chitinase 3-Like-1 Inhibits Cell Proliferation, Promotes Apoptosis, and Enhances Effect of Anti-Programmed Death Ligand 1 (PD-L1) in Diffuse Large B Cell Lymphoma Cells. Yang Xiao,Fang Dong,Li Ming,Chen Jiayi,Cheng Yuanbo,Luo Jianming Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Enzymatically inactive chitinase-like protein CHI3L1 is overexpressed in diffuse large B cell lymphoma (DLBCL) patients with PD-L1 imbalance and promotes tumor progression in the microenvironment. Based on this, we investigated how CHI3L1 acts on the proliferation and apoptosis of DLBCL and whether there is a synergy of CHI3L1 in combination with anti-PD-L1 antibodies in vivo. MATERIAL AND METHODS CHI3L1 was detected by quantitative real-time PCR (RT-PCR) and western blot (WB) in B-lymphoma cell lines. CHI3L1 interference plasmids were constructed, and the levels of proliferation, cell cycle, apoptosis, and cell survival were examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model by RT-PCR, WB, CCK-8, and flow cytometry. RESULTS CHI3L1 was significantly expressed in SU-DHL-4 cells. CHI3L1-interfered RNA ShRNA-CHI3L1-1 was chosen to be used in the next experiment because it had a better interference effect. Dampened cell proliferation level, arrested cell cycle, reduced protein expressions of cyclin D1 and cyclin D2, and promoted cell apoptosis level were observed after SU-DHL-4 was transfected with ShRNA-CHI3L1-1. Furthermore, we also noticed increased expression of Bcl-2, decreased expressions of bax, cleaved caspase 3 and cleaved PARP, promoted cell survival-related protein p53, and reduced survivin. CONCLUSIONS This study demonstrated that knockdown of CHI3L1 inhibits cancer cell proliferation by regulating cell cycles, promotes cancer cell apoptosis, and enhances the pro-apoptotic effect of anti-PD-L1 antibody both in vivo and in vitro in DLBCL. 10.12659/MSM.929431
    Knockdown of lncRNA MNX1-AS1 suppresses cell proliferation, migration, and invasion in prostate cancer. Li Zongwu,Wang Fangfei,Zhang Shibao FEBS open bio Altered expression of long non-coding RNAs (lncRNAs) has been reported in many malignancies, including prostate cancer. However, the role of lncRNA MNX1-AS1 in prostate cancer has not been reported. Here, we report that MNX1-AS1 is expressed in prostate cancer tissues and cells and that siRNA-mediated knockdown of MNX1-AS1 inhibits proliferation, migration, and invasion of prostate cancer DU145 and PC3 cells. In addition, down-regulation of MNX1-AS1 decreased expression of proliferating cell nuclear antigen, PH-3, N-cadherin, and vimentin, but enhanced expression of E-cadherin. In conclusion, this is the first report that knockdown of MNX1-AS1 suppresses prostate cancer cell proliferation, migration, and invasion. We believe that MNX1-AS1 may be a potential new therapeutic target for prostate cancer patients. 10.1002/2211-5463.12611
    miR-206 Inhibits Cell Proliferation and Extracellular Matrix Accumulation by Targeting Hypoxia-Inducible Factor 1-alpha (HIF-1α) in Mesangial Cells Treated with High Glucose. Cao Yanchao,Cao Xufen,Sun Lina,Li Yuanjie Medical science monitor : international medical journal of experimental and clinical research BACKGROUND The goal of this study was to investigate the expression of miR-206 in human glomerular mesangial cells (hMCs) treated by exposure to high glucose (HG) levels, to assess the influence of miR-206 on the proliferation and extracellular matrix (ECM) deposition of hMCs, and to investigate the potential mechanisms of action. MATERIAL AND METHODS The level of miR-206 was detected by RT-qPCR. MTT assay and colony formation assay were used to assess hMCs cell proliferation ability. Western blotting was carried out to measure the expression of related proteins. Bioinformatics software (http://www.targetscan.org) was used to predict the potential target genes of miR-206, and dual-luciferase reporter assay was used to confirm this prediction. RESULTS Our results suggest that the level of miR-206 was downregulated in HG-treated hMCs. Cell proliferation was promoted in HG-induced hMCs, while this phenomenon was significantly reversed with miR-206 mimics. miR-206 mimics significantly enhanced p21 expression and decreased cyclin D1 and CDK2 expressions, but the opposite was found in HG-induced hMCs. Moreover, the level of ECM proteins was notably increased in hMCs treated with HG, which was also significantly reversed by miR-206 mimics. miR-206 inhibitor had the opposite effects. Furthermore, HIF-1alpha was found to be a direct target of miR-206, and was negatively regulated by miR-206 in hMCs. miR-206 can target HIF-1alpha to modulate cell proliferation and ECM accumulation. CONCLUSIONS Collectively, our results suggest that miR-206 plays a vital role in HG-treated hMCs through inhibiting cell proliferation and ECM accumulation, partly via targeting HIF-1alpha. 10.12659/MSM.918912
    GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway. Zhang Zhihua,Zhang Rongjuan,Hao Changlai,Pei Xiaochuan,Li Jundong,Wang Lihong Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Multiple myeloma is featured by the proliferation of malignant plasma cell in bone marrow. We aimed to demonstrate the effects of valproic acid combined with GANT61 on multiple myeloma cell proliferation and clarify its mechanism. MATERIAL AND METHODS Multiple myeloma cells were exposed to valproic acid, GANT61, or the combination of valproic acid and GANT61, respectively. MTT assay was performed to detect the cell viability. Quantitative reverse transcriptase polymerase chain reaction and western blotting were used to detect mRNA and expression levels of proteins in Hedgehog signaling pathway. The Q-value of the combination regime was calculated to evaluate the drug combination effect. RESULTS Both valproic acid and GANT61 alone inhibited multiple myeloma cell proliferation in a dose-dependent manner compared to the control. In the presence of GANT61 or not, valproic acid inhibited multiple myeloma cell proliferation in a time-dependent manner. These 2 drugs had a synergistic effect at valproic acid concentration of ≥4 mM. Expression analysis showed that valproic acid significantly inhibited the expression levels of PTCH1, GLI1, and HES-1. GANT61 enhanced the inhibition of Hedgehog signaling pathway mediated by valproic acid. CONCLUSIONS GANT61 and valproic acid inhibited multiple myeloma cell proliferation synergistically by inhibiting the Hedgehog signaling pathway. The present study may provide a combination regime for the therapy of multiple myeloma. 10.12659/MSM.920541