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Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma

Journal of Huazhong University of Science and Technology [Medical Sciences] volume 36, pages 494–500 (2016)Cite this article

Summary

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality in part due to its high resistance to chemotherapeutic drugs. The anti-apoptotic Mcl-1 expression has been reported as a resistance factor in various types of tumors. Here, we investigated the expression of Mcl-1 in hepatoma cells and HCC tissues and its relationship with p53, and analyzed the possibility of the gene as a molecular target for HCC therapy. HCC specimens of 30 patients were examined by immunohistochemistry for Mcl-1 and p53 expression. Mcl-1 expression in hepatoma cell lines was measured by RT-PCR and Western blotting. The suppression of Mcl-1 by RNA interference or specific phosphatidylinositol-3 kinase (PI3K) inhibitor, LY294002, was evaluated as monotherapy, and it was combined with mitomycin C (MMC) in treating hepatoma cell line HepG2. Cell viability and apoptosis were assessed by MTT and FACS analysis. Finally, changes of Mcl-1 or p53 expression in various hepatoma cell lines were examined after transfection with Mcl-1 siRNA, the Mcl-1 expression plasmid, or the wide-type p53 expression plasmid, respectively. Mcl-1 protein was remarkably enhanced in HCC tissues as compared with adjacent non-tumor liver tissues. In addition, Mcl-1 was prominently expressed in HepG2 and Hep3B cells, weakly in SMMC7721 cells, and not in L02 cells. P53 protein was also overexpressed in HCC tissues and there was a significant correlation between the expression of p53 and Mcl-1. Silencing Mcl-1 by RNAi or LY294002 downregulated Mcl-1 expression and led to decreased cell viability and increased apoptosis. Combination of MMC and Mcl-1 RNAi or LY294002 exhibited a significant chemosensitizing effect. The expression of p53 was not influenced by Mcl-1 siRNA in HepG2 cells or transfection with the Mcl-1 expression plasmid in L02 cells. Furthermore, the expression of Mcl-1 in Hep3B cells was also not significantly changed after transfection with the wild-type p53 expression plasmid. It is concluded that Mcl-1 is overexpressed in HCC tissues. The mechanisms by which silencing Mcl-1 sensitizes hepatoma cells towards chemotherapy may be not attributed to the upregulated expression of p53 but the dysfunction of p53 through Mcl-1/p53 interaction. Mcl-1 may be a potential target of gene therapy for HCC.

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Affiliations

  1. Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qin Yu, Zhao-Yu Liu, Qiong Chen & Ju-sheng Lin

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  1. Qin Yu
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  2. Zhao-Yu Liu
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  3. Qiong Chen
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  4. Ju-sheng Lin
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Correspondence to Ju-sheng Lin.

Additional information

This project was supported by a grant from the National Natural Science Foundation of China (No. 81400593).

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Yu, Q., Liu, ZY., Chen, Q. et al. Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 494–500 (2016). https://doi.org/10.1007/s11596-016-1614-7

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  • DOI: https://doi.org/10.1007/s11596-016-1614-7

Keywords

  • Mcl-1
  • potential target
  • hepatocellular carcinoma