OncoTargets and Therapy (Apr 2018)

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

  • Gao X,
  • Zhu Y,
  • Li JH,
  • Wang X,
  • Zhang X,
  • Yi C,
  • Yang X

Journal volume & issue
Vol. Volume 11
pp. 2227 – 2239

Abstract

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Xiao-Mei Gao,* Ying Zhu,* Jian-Hua Li,* Xiang-Yu Wang, Xiao-Fei Zhang, Chen-He Yi, Xin Yang Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China *These authors contributed equally to this work Aim: 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.Methods: 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.Results: 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.Conclusion: 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. Keywords: miR-26a, p53, Mcl1, mitochondrial apoptosis, hepatocellular carcinoma 

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