Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib
Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib
复制标题
miR-193b 的恢复使乙型肝炎病毒相关肝细胞癌对索拉非尼敏感。
DOI：
10.1016/j.canlet.2014.07.004
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发表时间：
2014-10-01
期刊：
影响因子：
9.7
通讯作者：
Xiao, Zhiyu
中科院分区：
文献类型：
--
作者：
Mao, Kai;Zhang, Jianlong;Xiao, Zhiyu
背景：慢性乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要危险因素。本研究旨在探讨索拉非尼耐药机制，寻找使hbv相关HCC对索拉非尼敏感化的有效策略。方法：在hbv阳性/阴性HCC细胞系中评估索拉非尼的细胞毒性。分别采用Q-PCR、原位杂交、western blot、免疫组化检测miR-193b和髓细胞白血病-1 （Mcl-1）蛋白的表达。我们使用Mcl-1 3'-UTR的荧光素酶报告基因作为miR-193b的靶标进行验证。流式细胞术、caspase-3活性测定、DAPI染色检测细胞凋亡。结果：HBV阳性HCC细胞对索拉非尼的IC50明显高于未感染HBV的HCC细胞。在hbv阳性的HCC细胞和组织中，miR-193b显著下调，Mcl-1水平升高。Mcl-1 3'-UTR报告基因的活性被miR-193b mimic共转染抑制。恢复miR-193b的表达使hbv相关的HCC细胞对索拉非尼治疗增敏，并促进索拉非尼诱导的细胞凋亡。结论：调节miRNAs表达可能是一种潜在的方法，可以增强对索拉非尼在hbv相关HCC中的应答。2014爱思唯尔爱尔兰有限公司版权所有。
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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.