Neoplastic interactions of hepatitis C virus with telomerase.

慢性丙型肝炎感染(丙型肝炎病毒)是一个世界性的健康问题，可能导致肝硬化，完 分期为肝病和肝细胞癌。由于丙型肝炎病毒的流行， 肝癌的发病率正在以惊人的速度上升，美国退伍军人患有肝硬变的寿命为5-8% 罹患肝细胞癌的风险。新的、高效的抗病毒疗法 最近出现了丙型肝炎病毒，但这些对肝细胞癌的发展几乎没有影响 而且，这种病毒是如何致癌的，几乎是未知的。我们小组一直在研究 丙型肝炎病毒对宿主细胞逆转录酶--端粒酶的影响 修复短染色体DNA的3‘端“端粒”结束于细胞分裂。适量端粒 必须保持长度，以避免染色体损伤并支持连续的细胞 复制。因此，端粒酶在大多数恶性肿瘤中被诱导或上调。 细胞，已被证明是检测癌症和抗癌的有价值的细胞靶酶。 心理治疗。 我们的实验室最近发现，丙型肝炎病毒感染后早期会诱导端粒酶，而我们 假设这一行为有助于病毒的致瘤性。端粒酶的诱导是 可能部分是通过宿主中的丙型肝炎病毒核心蛋白、NS5A和NS3-4A的作用而促成的 肝细胞。我们还证明了丙型肝炎病毒核心蛋白和NS5A蛋白在转录水平上 激活TERT启动子和病毒蛋白酶-解旋酶复合体NS3-4A结合 特异性地作用于TERT并刺激端粒酶催化活性。我们的数据最先表明 丙型肝炎病毒可以诱导TERT的表达，也可以催化激活宿主端粒酶。这个 这一应用的基础假设是，丙型肝炎病毒通过最初的 与Wnt/β-连环蛋白信号系统的相互作用进而驱动端粒酶逆转录酶启动子的开放 抄写。这很可能是由CORE和NS5A完成的，它们已经被证明是稳定的 激活Wnt/β-连环蛋白信号复合体。我们还假设NS3-4A，a 多功能蛋白酶-解旋酶，通过优化端粒酶活性提高端粒酶催化活性 酶的II型加工性。通过增加端粒酶活性，NS3-4A因此促进 端粒修复的效率和促进肿瘤进展。总体而言， 该病毒上调染色体维持和修复机制，并促进 肝癌的发生。我们工作的长期目标有两个：我们希望确定 病毒诱导端粒酶表达和增加端粒酶的机制 催化活性。这两个目标的实现将导致对细胞 这些事件对肝癌的发展和最终治疗无疑是重要的。这 方法对于理解丙型肝炎病毒如何促进肝癌是高度相关的，数据将 为最终靶向端粒酶或病毒解旋酶的药物奠定坚实的基础 抗癌剂。

Chronic hepatitis C infection (HCV) is a worldwide health problem that can lead to cirrhosis, end stage liver disease, and hepatocellular carcinoma (HCC). Because of the HCV epidemic, the incidence of HCC is rising at an alarming rate and US veterans with cirrhosis have 5-8% lifetime risk of developing hepatocellular carcinoma (HCC). New, highly effective, antiviral therapies for HCV have recently become available, but these have had little impact on development of HCC and it is virtually unknown how the virus causes cancer. Our group has been studying the effects of HCV on the host cellular enzyme telomerase, which is a reverse transcriptase (RT) that repairs short chromosomal DNA 3' “telomeric” ends in dividing cells. Adequate telomere lengths must be maintained to avoid chromosomal injury and to support continuous cellular replication. Consequently, telomerase is induced or upregulated in the majority of malignant cells and has proven to be a valuable cellular target enzyme for cancer detection and anticancer therapy. Our laboratory has recently shown that HCV induces telomerase early after infection and we hypothesize that this behavior contributes to the virus' oncogenicity. Induction of telomerase is likely facilitated in part through the actions of HCV proteins core, NS5A and NS3-4A in the host hepatocyte. We have also demonstrated that HCV core and NS5A proteins transcriptionally activate TERT promoter and that NS3-4A, the viral protease-helicase complex, binds specifically to TERT and stimulates telomerase catalytic activity. Our data are the first to show that HCV can induce TERT expression as well as catalytically activate host telomerase. The overlying hypothesis of this application is that HCV reactivates telomerase through initial interactions with the Wnt/β-catenin signaling system which then drives TERT promoter to open transcription. This is likely accomplished by core and NS5A which have been shown to stabilize activated Wnt/β-catenin signaling complexes. We also hypothesize that NS3-4A, a multifunctional protease-helicase, increases telomerase catalytic activity by optimizing the enzyme's type II processivity. By increasing telomerase processivity, NS3-4A thus promotes efficiency of telomere repair and facilitates neoplastic progression. Collectively, the actions of the virus upregulate chromosomal maintenance and repair mechanisms and promote hepatocarcinogenesis. The long term goals of our work are two-fold: we wish to determine the mechanisms of how the virus induces telomerase expression and increases telomerase catalytic activity. Achievement of both of these goals will lead to the identification of cellular events that are undoubtedly important for HCC development and ultimately treatment. This approach is highly relevant for understanding how HCV promotes liver cancer and the data will lay a firm foundation for eventual drug targeting of telomerase or the viral helicase with anticancer agents.