microRNA-26a induces a mitochondrial apoptosis mediated by p53 through targeting to inhibit Mcl1 in human hepatocellular carcinoma

• Published in: OncoTargets and therapy Vol. 11; pp. 2227 - 2239
• Main Authors: Gao, Xiao-Mei, Zhu, Ying, Li, Jian-Hua, Wang, Xiang-Yu, Zhang, Xiao-Fei, Yi, Chen-He, Yang, Xin
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2018; Dove Medical Press
• Subjects: 5-Fluorouracil; Apoptosis; Cancer therapies; Committees; Ethics; Experiments; Flow cytometry; Hepatitis; Kinases; Laboratory animals; Liver cancer; Metastasis; MicroRNAs; Original Research; Plasmids; Proteins; Thrombosis; Tumors; United States > US; China; miR-26a; hepatocellular carcinoma; mitochondrial apoptosis; Mcl1; p53
• ISSN: 1178-6930; 1178-6930
• DOI: 10.2147/OTT.S160895

We have previously found that microRNA-26a (miR-26a) is a potential tumor suppressor in hepatocellular carcinoma (HCC). In this study, we further explored the roles of miR-26a in HCC apoptosis. miR-26a expression levels were detected in HCC tissues by real-time PCR. Statistical analysis was performed to explore the correlation between miR-26a expression and apoptotic cells and the antiapoptotic protein levels. In vitro assays were performed to investigate the roles of miR-26a in HCC apoptosis. The immunohistochemical staining analysis, Western blot, and luciferase reporter assay were performed to evaluate the relationship between miR-26a and its potential upstream regulating and downstream target genes. The potential mechanism of the combination treatment of interferon-α1b (IFN-α1b) and 5-fluorouracil (5-FU) was explored by in vitro and in vivo assays. miR-26a levels were significantly associated with the number of apoptotic cells and inversely correlated with the protein levels of Bcl-2, Bcl-xL, and Mcl1 in HCC tissues. Furthermore, miR-26a was proved to induce the mitochondrial apoptosis in vitro by directly targeting to inhibit Mcl1 in HCC cells. Moreover, p53 was demonstrated to mediate miR-26a-induced apoptosis, by activating its promoter in HCC. Meanwhile, the combination treatment of IFN-α1b and 5-FU could induce the expression of p53, which then upregulated miR-26a and downregulated Mcl1 levels, and finally promoted the apoptosis of HCC cells through a mitochondrial pathway. These findings highlight the important and related molecular mechanism of miR-26a in the regulation of apoptosis and implicate the potential application of combination of IFN-α1b and 5-FU in HCC treatment.