Department of Microbiology, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
Cancer Lett. 2012 Aug 28;321(2):154-61. doi: 10.1016/j.canlet.2012.01.044. Epub 2012 Feb 7.
Hepatitis C virus Core plays a vital role in the development of hepatocellular carcinoma; however, the mechanism is still controversial. Here, we show that Core overcomes premature senescence provoked by a reactive oxygen species inducer, H2O2, in human liver cells. For this effect, Core down-regulated levels of p16 via promoter hypermethylation and subsequently induced phosphorylation of Rb in the presence of H2O2. Levels of p21 and p27, however, were little affected by Core under the condition. The potentials of Core to inactivate Rb and suppress H2O2-mediated cellular senescence were abolished when levels of p16 were recovered by either exogenous complementation or inhibition of DNA methylation. Considering that cellular senescence provoked by oxidative stresses is an important tumor suppression process, our present study provides a new strategy by which HCV promotes development of hepatocellular carcinoma.
丙型肝炎病毒核心在肝细胞癌的发展中起着至关重要的作用，但机制仍存在争议。在这里，我们发现核心可以克服由活性氧诱导剂 H2O2 引起的人类肝细胞过早衰老。为了达到这种效果，核心通过启动子超甲基化降低了 p16 的水平，随后在 H2O2 的存在下诱导了 Rb 的磷酸化。然而，在这种情况下，p21 和 p27 的水平受核心的影响很小。当通过外源补充或抑制 DNA 甲基化恢复 p16 水平时，核心使 Rb 失活和抑制 H2O2 介导的细胞衰老的潜力被消除。考虑到氧化应激引起的细胞衰老，是一种重要的肿瘤抑制过程，我们的研究为丙型肝炎病毒促进肝细胞癌发展提供了一种新的策略。
