Kai Mao1, Jianlong Zhang1, Chuanchao He1, Kang Xu1, Jieqiong Liu2, Jian Sun1, Gang Wu3, Cui Tan4, Yunjie Zeng4, Jie Wang5, Zhiyu Xiao6. 1. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 2. Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 3. Department of Hepatobiliary Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China. 4. Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 5. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: sumsjw@163.com. 6. Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: xzysurgeon@163.com.
Abstract
BACKGROUND: Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV-associated HCC to sorafenib. METHODS: Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3'-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining. RESULT: The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3'-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis. CONCLUSIONS: Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC.
BACKGROUND:Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV-associated HCC to sorafenib. METHODS:Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3'-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining. RESULT: The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3'-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis. CONCLUSIONS: Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC.
Authors: Chung Man Chan; Kenneth K Y Lai; Enders K O Ng; Mei Na Kiang; Tiffany W H Kwok; Hector K Wang; Kwok Wah Chan; Tsz Ting Law; Daniel K Tong; Kin Tak Chan; Nikki P Lee; Simon Law Journal: Oncol Lett Date: 2017-12-27 Impact factor: 2.967