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

Abstract

// Yong Wang 1, * , Baocun Sun 1, 2, 3, * , Xiulan Zhao 1, 3 , Nan Zhao 1 , Ran Sun 1 , Dongwang Zhu 4 , Yanhui Zhang 2 , Yanlei Li 1 , Qiang Gu 1, 3 , Xueyi Dong 1, 3 , Meili Wang 1 , Jindan An 5 1 Department of Pathology, Tianjin Medical University, Tianjin 300070, China 2 Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China 3 Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China 4 Department of Prosthodontics, Affiliated Stomatological Hospital, Tianjin Medical University, Tianjin 300070, China 5 Department of Pathology, Mudanjiang Medical University, Heilongjiang 157011, China * These authors contributed equally to this work Correspondence to: Baocun Sun, e-mail: baocunsun@aliyun.com Keywords: microRNA, SMAD1, epithelial-mesenchymal transition, early recurrence, hepatocellular carcinoma Received: September 30, 2015      Accepted: March 04, 2016      Published: March 24, 2016 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.