Twist1-related miR-26b-5p suppresses epithelial-mesenchymal transition, migration and invasion by targeting SMAD1 in hepatocellular carcinoma
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Yong Wang1,*, Baocun Sun1,2,3,*, Xiulan Zhao1,3, Nan Zhao1, Ran Sun1, Dongwang Zhu4, Yanhui Zhang2, Yanlei Li1, Qiang Gu1,3, Xueyi Dong1,3, Meili Wang1, Jindan An5
1Department of Pathology, Tianjin Medical University, Tianjin 300070, China
2Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China
3Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin 300052, China
4Department of Prosthodontics, Affiliated Stomatological Hospital, Tianjin Medical University, Tianjin 300070, China
5Department of Pathology, Mudanjiang Medical University, Heilongjiang 157011, China
*These authors contributed equally to this work
Baocun Sun, e-mail: firstname.lastname@example.org
Keywords: microRNA, SMAD1, epithelial-mesenchymal transition, early recurrence, hepatocellular carcinoma
Received: September 30, 2015 Accepted: March 04, 2016 Published: March 24, 2016
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.
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