Twist1-related miR-26b-5p suppresses epithelial-mesenchymal transition, migration and invasion by targeting SMAD1 in hepatocellular carcinoma.

Xiulan Zhao,Dongwang Zhu,Nan Zhao,Jindan An,Meili Wang,Yanlei Li,Yanhui Zhang,Xueyi Dong,Baocun Sun,Ran Sun,Qiang Gu,Yong Wang

doi:10.18632/oncotarget.8328

Xiulan Zhao, Dongwang Zhu + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.8328

Copy DOI

Abstract

Twist1 is well known to induce epithelial-mesenchymal transition (EMT) and promote tumor metastasis. MicroRNAs (miRNAs) are involved in the EMT process and are associated with metastasis in hepatocellular carcinoma (HCC). In the present study, microRNA-26b-5p (miR-26b-5p) expression was consistently and significantly downregulated in HepG2-Twist1 HCC cell lines compared with HepG2-vector cell lines using microarrays (the HepG2-Twist1 cell line can stably express Twist1). miR-26b- 5p downregulation was directly mediated by Twist1 through binding to the promoter region of miR-26b-5p in HepG2-Twist1 cells by ChIP-seq technology. Both gain- and loss-of-function studies showed that miR-26b-5p dramatically suppressed EMT and the invasion ability of HCC cells in vitro. Using mouse models, tumors derived from miR- 26b-5p-overexpressed HCC cells exhibited a significant reduction in tumorigenicity compared with the control group. Subsequent investigation revealed that miR-26b-5p directly inhibited SMAD family member 1 (SMAD1) expression. miR-26b-5p repressed BMP4/Smad1 signaling following SMAD1 inhibition. Overexpression of SMAD1 reversed the function of miR-26b-5p. In human HCC tissues and mouse xenograft tumors, miR-26b-5p levels were inversely correlated with SMAD1 expression as well as metastasis. Conclusion: miR-26b-5p suppresses Twist1-induced EMT, invasion, and metastasis of HCC cells by targeting SMAD1 and BMP4/Smad1 signaling. This suggests a promising application for miR-26b-5p in anti-HCC therapy.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of death from cancer worldwide
To screen miRNA-related mechanisms underlying epithelial-mesenchymal transition (EMT) followed by the upregulation of Twist1, we performed microarray miRNA analysis on HepG2-vector and HepG2-Twist1 human hepatocellular carcinoma (HCC) cell lines
The results obtained from HCC patients were consistent with previous observations that the expression of miR-26b-5p was significantly downregulated in HCC tissues (Figure 1C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of death from cancer worldwide. The ability of some miRNAs to function as tumor promoters or suppressors in hepatocarcinogenesis has led to new insights into the molecular pathways involved in HCC [3, 4]. Up to 90% of all human cancers, including HCC, are carcinomas, which are cell growths that originate in epithelial cells. Epithelial-mesenchymal transition (EMT), a normal embryological process, is frequently implicated in cancer aggressiveness and metastasis. It is characterized by loss of cell adhesion, www.impactjournals.com/oncotarget repression of E-cadherin expression, acquisition of the mesenchymal marker vimentin, and increased cell motility and invasiveness [5]. MiRNAs have been demonstrated to exert important regulatory functions in EMT [6]

Methods

Results

Conclusion