MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2.

De-Ning Ma,Zhao-You Tang,Wei-Ping Zhu,Cheng-Hao Wang,Hui-Chuan Sun,Cheng-Dong Qin,Man-Qing Cao,Xiao-Dong Zhu,Ning Zhang,Dong-Mei Gao,Bo-Gen Ye,Di-Hua Zhan,Zong-Tao Chai,Yi-Ming Zhao

doi:10.1186/s13045-015-0229-y

Abstract

BackgroundOur previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). The direct roles of miR-26a on tumor cell invasion remain poorly understood. In this study, we aim to explore the mechanism of miR-26a in modulating epithelial-mesenchymal transition (EMT) in HCC.MethodsIn vitro cell morphology and cell migration were compared between the hepatoma cell lines HCCLM3 and HepG2, which were established in the previous study. Overexpression and down-regulation of miR-26a were induced in these cell lines, and Western blot and immunofluorescence assays were used to detect the expression of EMT markers. Xenograft nude mouse models were used to observe tumor growth and pulmonary metastasis. Immunohistochemical assays were conducted to study the relationships between miR-26a expression and enhancer of zeste homolog 2 (EZH2) and E-cadherin expression in human HCC samples.ResultsDown-regulation of miR-26a in HCCLM3 and HepG2 cells resulted in an EMT-like cell morphology and high motility in vitro and increased in tumor growth and pulmonary metastasis in vivo. Through down-regulation of EZH2 expression and up-regulation of E-cadherin expression, miR-26a inhibited the EMT process in vitro and in vivo. Luciferase reporter assay showed that miR-26a directly interacted with EZH2 messenger RNA (mRNA). Furthermore, the expression of miR-26a was positively correlated with E-cadherin expression and inversely correlated with EZH2 expression in human HCC tissue.ConclusionsmiR-26a inhibited the EMT process in HCC by down-regulating EZH2 expression.

Highlights

Our previous study reported that microRNA-26a inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC)
We found that miR-26a indirectly suppresses tumor progress in HCC by inhibiting tumor angiogenesis and suppressing intratumoral macrophage infiltration [14, 18]
Down-regulation of miR-26a is associated with epithelial-mesenchymal transition (EMT) in tumor cells In our previous study [18], the expression levels of miR26a were modified in two human hepatoma cell lines, HepG2 and HCCLM3, and subclones with stable expression of miR-26a were established

Summary

Introduction

Our previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). EMT is a transient and reversible switch from a polarized and epithelial phenotype to a fibroblastoid or mesenchymal cellular phenotype, with the latter showing highly motile and invasive properties [8, 9] This process is a fundamental event both in the early stage of embryonic development and in pathophysiological situations, including wound healing, chronic inflammation, and carcinoma progression [7]. MicroRNAs (miRNAs) are an evolutionarily conserved family of small (a class of 22-nucleotide) noncoding RNAs, known to be potent modifiers of gene expression at a posttranscriptional level They regulate multiple cellular processes such as tumorigenesis and metastasis by down-regulating gene expression in various malignancies, including HCC [13]. We aimed to investigate the functional role of miR-26a in EMT and consider its potential as a therapeutic target in HCC

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