MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis.

Cholangiocarcinoma (CCA) is a lethal cancer associated with chronic inflammation that has increased in prevalence in recent decades. The dysregulated expression of microRNAs (miRNAs) has been detected in various types of malignancies, and depending on the target genes this can result in miRNAs functioning as tumor suppressors or oncogenes. In this study, we investigated the role of miR-124 in cholangiocarcinoma (CCA) and found that its expression was significantly downregulated in the tumor tissue of patients and in CCA cell lines. Our results provided evidence that miR-124 induces apoptotic cell death and triggers the autophagic flux in CCA cells. EZH2 and STAT3 were identified as direct targets of miR-124. The effect of miR-124 on EZH2 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Silencing of EZH2 restored the effects of miR-124, whereas overexpression of EZH2 abrogated the effects of miR-124. Silencing of Beclin1 or ATG5 abrogated the effects of miR-124 or siEZH2. In vivo, overexpression of miR-124 dramatically induced autophagy-related cell death and suppressed tumorigenicity. Taken together, our findings indicated that downregulation of miR-124 expression was associated with disease progression in human CCA and we revealed that miR-124 exerts a tumor suppressive function in CCA by inducing autophagy-related cell death via direct targeting of the EZH2-STAT3 signaling axis.

Ma J ，Weng L ，Wang Z ，Jia Y ，Liu B ，Wu S ，Cao Y ，Sun X ，Yin X ，Shang M ，Mao A ... -  《-》

Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway.

Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice. We identified three key components of the Notch pathway, Notch1, Notch2, and Jagged 1, as direct targets of miR-34a. Our further studies show that down-regulation of miR-34a is caused by Enhancer of zeste homolog 2 (EZH2)-mediated H3 lysine 27 trimethylation as well as DNA methylation. Accordingly, treatment with the EZH2 inhibitor, selective S-adenosyl-methionine-competitive small-molecule (GSK126), or the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, partially restored miR-34a levels in human CCA cells. Immunohistochemical staining and Western blot analyses showed increased EZH2 expression in human CCA tissues and cell lines. We observed that GSK126 significantly reduced CCA cell growth in vitro and intrahepatic metastasis in vivo. Our findings provide novel evidence that miR-34a expression is silenced epigenetically by EZH2 and DNA methylation, which promotes CCA cell growth through activation of the Notch pathway. Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA.

Kwon H ，Song K ，Han C ，Zhang J ，Lu L ，Chen W ，Wu T ... -  《-》

Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma.

Lin KY ，Ye H ，Han BW ，Wang WT ，Wei PP ，He B ，Li XJ ，Chen YQ ... -  《-》

Let-7c inhibits cholangiocarcinoma growth but promotes tumor cell invasion and growth at extrahepatic sites.

Xie Y ，Zhang H ，Guo XJ ，Feng YC ，He RZ ，Li X ，Yu S ，Zhao Y ，Shen M ，Zhu F ，Wang X ，Wang M ，Balakrishnan A ，Ott M ，Peng F ，Qin RY ... -  《Cell Death & Disease》

SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma.

Xu Y ，Yao Y ，Jiang X ，Zhong X ，Wang Z ，Li C ，Kang P ，Leng K ，Ji D ，Li Z ，Huang L ，Qin W ，Cui Y ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》