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

Abstract

UNLABELLED:

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.

• Authors: Yong Wang, Baocun Sun, Xiulan Zhao, Nan Zhao, Ran Sun, Dongwang Zhu, Yanhui Zhang, Yanlei Li, Qiang Gu, Xueyi Dong, Meili Wang, Jindan An
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 17 Pg. 24383-401 (Apr 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27027434 (Publication Type: Journal Article)

Chemical References

• 3' Untranslated Regions
• MIRN26A microRNA, human
• MicroRNAs
• Nuclear Proteins
• Smad1 Protein
• TWIST1 protein, human
• Twist-Related Protein 1

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms (genetics, metabolism, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Neoplasm Invasiveness
• Nuclear Proteins (genetics, metabolism)
• RNA Interference
• Smad1 Protein (genetics, metabolism)
• Transplantation, Heterologous
• Twist-Related Protein 1 (genetics, metabolism)