miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.
miR-370 regulates ISG15 expression and influences IFN-α sensitivity in hepatocellular carcinoma cells.
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miR-370调节ISG15表达并影响肝细胞癌细胞中IFN-α敏感性
DOI：
10.3233/cbm-171075
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xia M
中科院分区：
文献类型：
--
作者：
Liu Z;Ma M;Yan L;Chen S;Li S;Yang D;Wang X;Xiao H;Deng H;Zhu H;Zuo C;Xia M
干扰素是肝细胞癌化疗和放射治疗的辅助药物，但部分肝细胞癌患者对干扰素治疗无效。我们进行了功能丧失和功能获得实验，以检测ISG15在LH86、HLCZ01、SMMC7721和Huh7细胞株和肿瘤样本对干扰素敏感性中的作用。在有干扰素存在的情况下，ISG15的过表达减少了HuH7和LH86细胞的凋亡，而shRNA介导的ISG15表达下调增加了HuH7和LH86细胞的凋亡。我们在ISG15基因的3‘-非编码区发现了一个可能的miR-370靶点，并且miR-370在肝癌细胞系中的表达水平反映了每个细胞株在干扰素诱导的细胞凋亡中的水平。肝癌细胞系和肿瘤组织中miR-370的表达水平均显著低于对照细胞和组织(0.05)。在干扰素处理的LH86和Huh7细胞中，miR-370的过表达增加了LH86和Huh7细胞的凋亡率，并减少了经干扰素处理的小鼠LH86和Huh7来源的移植瘤的体积。我们的研究结果表明miR-370作为一种肝癌肿瘤抑制因子和干扰素敏感性的调节因子发挥作用，并且miR-370可能是一种有用的肝癌患者预后标志物。
Interferon- (IFN-) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-. We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN- sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples. The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells. We identified a putative miR-370 target site in the 3’-UTR in the ISG15 mRNA, and the level of miR-370 expression in HCC cell lines reflected the level of IFN--induced apoptosis exhibited by each. Both HCC cell lines and tumor samples had significantly lower levels of miR-370 than the control cells and tissues ( 0.05). The overexpression of miR-370 in IFN--treated LH86 and Huh7 cells increased apoptosis and reduced the volume of LH86- and Huh7-derived xenograft tumors in mice treated with IFN- compared with the control tumors. Our findings suggest that miR-370 functions as an HCC tumor suppressor and regulator of IFN- sensitivity and that miR-370 might be a useful prognostic marker for HCC patients.