Mcl-1 as a potential therapeutic target for human hepatocelluar carcinoma.
10.1007/s11596-016-1614-7
- Author:
Qin YU
1
;
Zhao-Yu LIU
1
;
Qiong CHEN
1
;
Ju-Sheng LIN
2
Author Information
1. Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
2. Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. jslin@tjh.tjmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Mcl-1;
hepatocellular carcinoma;
potential target
- MeSH:
Adenoma, Liver Cell;
drug therapy;
genetics;
pathology;
Apoptosis;
drug effects;
Biomarkers, Tumor;
biosynthesis;
genetics;
Chromones;
administration & dosage;
Gene Expression Regulation, Neoplastic;
drug effects;
Hep G2 Cells;
Humans;
Liver Neoplasms;
drug therapy;
genetics;
pathology;
Morpholines;
administration & dosage;
Myeloid Cell Leukemia Sequence 1 Protein;
biosynthesis;
genetics;
RNA, Small Interfering;
genetics;
Transfection;
Tumor Suppressor Protein p53;
biosynthesis;
genetics
- From:
Journal of Huazhong University of Science and Technology (Medical Sciences)
2016;36(4):494-500
- CountryChina
- Language:English
-
Abstract:
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.
