Institute of Genomic Medicine, Wenzhou Medical College, 268 Xueyuan Road, Wenzhou, Zhejiang Province 325000, P.R. China.
Carcinogenesis. 2014 Jan;35(1):155-63. doi: 10.1093/carcin/bgt268. Epub 2013 Aug 5.
Hepatitis B surface antigen (HBsAg) seropositivity is an important risk factor for hepatocellular carcinoma (HCC), and HBsAg-transgenic mice have been reported to spontaneously develop HCC. The major histocompatibility complex class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, we found that HBsAg overexpression in HepG2 cells led to upregulation of 133 and downregulation of 9 microRNAs (miRNAs). Interestingly, several HBsAg-induced miRNAs repressed the expression of MICA and MICB via targeting their 3'-untranslated regions. In addition, the expression of MICA and MICB was significantly reduced upon HBsAg overexpression, which was partially restored by inhibiting the activities of HBsAg-induced miRNAs. Moreover, HBsAg-overexpressing HCC cells exhibited reduced sensitivity to natural killer cell-mediated cytolysis. Taken together, our data suggest that HBsAg supresses the expression of MICA and MICB via induction of cellular miRNAs, thereby preventing NKG2D-mediated elimination of HCC cells.
乙型肝炎表面抗原（HBsAg）阳性是肝细胞癌（HCC）的重要危险因素，已有报道称 HBsAg 转基因小鼠会自发发生 HCC。主要组织相容性复合体 I 类相关分子 A 和 B（MICA 和 MICB）是 NKG2D 的配体，在肿瘤免疫监视中发挥重要作用。在本研究中，我们发现 HepG2 细胞中 HBsAg 的过表达导致 133 个 miRNA 的上调和 9 个 miRNA 的下调。有趣的是，一些 HBsAg 诱导的 miRNA 通过靶向它们的 3'-UTR 抑制 MICA 和 MICB 的表达。此外，HBsAg 过表达后 MICA 和 MICB 的表达显著降低，通过抑制 HBsAg 诱导的 miRNA 的活性部分恢复。此外，HBsAg 过表达的 HCC 细胞对自然杀伤细胞介导的细胞溶解的敏感性降低。总之，我们的数据表明，HBsAg 通过诱导细胞 miRNA 抑制 MICA 和 MICB 的表达，从而防止 NKG2D 介导的 HCC 细胞消除。
