State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
J Biol Chem. 2013 Jun 21;288(25):18484-93. doi: 10.1074/jbc.M113.458158. Epub 2013 May 6.
Hepatitis B virus (HBV) is a key risk factor for the development of hepatocellular carcinoma (HCC). Recent work suggests a functional link between HCC and microRNA expression, but the mechanism underlying the functional interaction between microRNA and HBV infection has remained largely elusive. Here we present evidence that the microRNA machinery serves as a defense system against HBV infection, which, in turn, reprograms the expression of specific microRNAs. We demonstrate a critical role of miR-15a/miR-16-1 in this functional interplay between microRNA and HBV infection, but in contrast to various indirect mechanisms mediated by viral proteins, we unexpectedly found that the HBx transcript directly triggers the down-regulation of miR-15a/miR-16-1 via the microRNA targeting sequences in the viral RNA. Because miR-15a and miR-16-1 are well known tumor suppressor microRNAs in multiple human cancers, our findings raise the intriguing possibility that viral RNA-mediated down-regulation of specific tumor suppressor microRNAs may contribute to HCC development in HBV-infected cells.
乙型肝炎病毒 (HBV) 是肝细胞癌 (HCC) 发展的一个关键风险因素。最近的研究表明 HCC 与 microRNA 表达之间存在功能联系，但 microRNA 与 HBV 感染之间功能相互作用的机制在很大程度上仍未被揭示。在这里，我们提供的证据表明 microRNA 机制是针对 HBV 感染的防御系统，而 HBV 感染又会重新编程特定 microRNA 的表达。我们证明了 miR-15a/miR-16-1 在 microRNA 与 HBV 感染之间的这种功能相互作用中起着关键作用，但与病毒蛋白介导的各种间接机制不同，我们出人意料地发现 HBx 转录本通过病毒 RNA 中的 microRNA 靶向序列直接触发 miR-15a/miR-16-1 的下调。因为 miR-15a 和 miR-16-1 是多种人类癌症中众所周知的肿瘤抑制 microRNAs，我们的发现提出了一个有趣的可能性，即病毒 RNA 介导的特定肿瘤抑制 microRNAs 的下调可能有助于 HBV 感染细胞中 HCC 的发展。
