Neoplastic interactions of hepatitis C virus with telomerase.

慢性丙型肝炎感染（HCV）是一个世界性的健康问题，可导致肝硬化， 分期肝病和肝细胞癌（HCC）。由于HCV的流行， HCC的发病率正在以惊人的速度上升，美国退伍军人肝硬化患者中有5-8%的人终生患有HCC。 发生肝细胞癌（HCC）的风险。新型高效抗病毒疗法， HCV是最近才出现的，但它们对HCC的发展几乎没有影响 病毒是如何导致癌症的，这几乎是未知的。我们小组一直在研究 HCV对宿主细胞端粒酶的影响，端粒酶是一种逆转录酶（RT） 在分裂细胞中修复短的染色体DNA 3'“端粒”末端。适当端粒 长度必须保持，以避免染色体损伤，并支持连续的细胞 复制的因此，端粒酶在大多数恶性肿瘤中被诱导或上调， 已被证明是一种有价值的细胞靶酶，用于癌症检测和抗癌 疗法 我们的实验室最近表明，HCV感染后早期诱导端粒酶， 假设这种行为有助于病毒的致癌性。端粒酶的诱导是 可能部分通过宿主中HCV蛋白核心、NS 5A和NS 3 -4A的作用而促进 肝细胞我们还证明了HCV核心和NS 5A蛋白在转录水平上与HCV的转录水平相关。 激活TERT启动子和病毒蛋白酶-解旋酶复合物NS 3 -4A结合 特异性地与TERT结合并刺激端粒酶催化活性。我们的数据首次显示 HCV可以诱导端粒酶活性的表达，并能催化激活宿主端粒酶活性。的 本申请的一个重要假设是HCV通过初始的端粒酶激活端粒酶， 与Wnt/β-catenin信号系统相互作用，然后驱动TERT启动子打开 转录。这可能是由核心和NS 5A完成的，它们已被证明是稳定的。 激活Wnt/β-catenin信号复合物。我们还假设NS 3 -4A，a 多功能蛋白酶-解旋酶，通过优化 酶的II型持续合成能力。通过增加端粒酶的持续合成能力，NS 3 -4A因此促进 端粒修复的效率和促进肿瘤进展。总的来说， 该病毒上调染色体维持和修复机制，并促进 肝癌发生我们工作的长期目标有两个方面：我们希望确定 病毒如何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识别细胞 这些事件对于HCC的发展和最终治疗无疑是重要的。这 这种方法与理解HCV如何促进肝癌高度相关，数据将 为端粒酶或病毒解旋酶的最终药物靶向奠定了坚实的基础， 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.