Neoplastic interactions of hepatitis C virus with telomerase.

丙型肝炎病毒与端粒酶的肿瘤相互作用。

• 批准号: 10047694
• 负责人: WARREN N SCHMIDT
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047694
• 关键词: Achievement; Antineoplastic Agents; Antiviral Agents; Antiviral Therapy; Behavior; Binding; Biopsy Specimen; Cancer Detection; Cancer Etiology; Cells; Chronic Hepatitis C; Cirrhosis; Complex; Core Protein; DNA; Data; Development; Drug Targeting; Enzymes; Epidemic; Event; Foundations; Future; Genetic Transcription; Goals; Grant; Health; Hepatitis C; Hepatitis C Therapy; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Holoenzymes; Human; In Vitro; Incidence; Infection; Injury; Laboratories; Lead; Length; Liver; Liver diseases; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Mus; Neoplasms; Nuclear; Oncogenic Viruses; Patients; Peptide Hydrolases; Primary carcinoma of the liver cells; Proteins; RNA-Directed DNA Polymerase; Signal Transduction; Structure; System; Telomerase; Transcriptional Activation; Transcriptional Regulation; Veterans; Viral; Viral Core Proteins; Virus; WNT Signaling Pathway; Work; beta catenin; cancer cell; cancer therapy; cellular targeting; experimental study; helicase; humanized mouse; in vivo; lifetime risk; mouse model; neoplastic; prevent; promoter; repair function; repaired; telomere; tumor progression; virtual

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.

慢性丙型肝炎感染（HCV）是一个全球性的健康问题，可导致肝硬化，最终 阶段肝病和肝细胞癌（HCC）。由于丙肝病毒的流行， HCC 发病率正以惊人的速度上升，患有肝硬化的美国退伍军人寿命缩短 5-8% 罹患肝细胞癌 (HCC) 的风险。新的、高效的抗病毒疗法 HCV最近出现了，但这些对HCC的发展影响不大 而且人们几乎不知道这种病毒是如何导致癌症的。我们组一直在研究 HCV 对宿主细胞端粒酶（一种逆转录酶 (RT)）的影响 修复分裂细胞中短染色体 DNA 3'“端粒”末端。足够的端粒 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细胞中被诱导或上调。 细胞并已被证明是用于癌症检测和抗癌的有价值的细胞靶酶 治疗。 我们的实验室最近表明，HCV 在感染后早期就会诱导端粒酶，我们 假设这种行为导致了病毒的致癌性。端粒酶的诱导是 可能部分是通过宿主中 HCV 蛋白核心、NS5A 和 NS3-4A 的作用来促进的 肝细胞。我们还证明了 HCV 核心蛋白和 NS5A 蛋白在转录上 激活 TERT 启动子并且 NS3-4A（病毒蛋白酶-解旋酶复合物）结合 特异性针对 TERT 并刺激端粒酶催化活性。我们的数据率先展现 HCV 可以诱导 TERT 表达并催化激活宿主端粒酶。这 本申请的基本假设是 HCV 通过初始端粒酶重新激活端粒酶。 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 core 和 NS5A 完成的，它们已被证明可以稳定 激活的 Wnt/β-连环蛋白信号复合物。我们还假设 NS3-4A 多功能蛋白酶解旋酶，通过优化端粒酶提高端粒酶催化活性 酶的 II 型持续合成能力。通过增加端粒酶的持续合成能力，NS3-4A 从而促进 端粒修复的效率并促进肿瘤进展。总的来说，行动 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：我们希望确定 病毒如何诱导端粒酶表达并增加端粒酶的机制 催化活性。这两个目标的实现将导致细胞的鉴定 毫无疑问，这些事件对 HCC 的发展和最终治疗很重要。这 方法对于了解 HCV 如何促进肝癌高度相关，并且数据将 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。

项目成果

Finally sofosbuvir: an oral anti-HCV drug with wide performance capability.

• DOI: 10.2147/pgpm.s52629
• 发表时间: 2014
• 期刊: Pharmacogenomics and personalized medicine
• 影响因子: 1.9
• 作者: Kayali Z;Schmidt WN
• 通讯作者: Schmidt WN

HCV Induces Telomerase Reverse Transcriptase, Increases Its Catalytic Activity, and Promotes Caspase Degradation in Infected Human Hepatocytes.

• DOI: 10.1371/journal.pone.0166853
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhu Z;Tran H;Mathahs MM;Moninger TO;Schmidt WN
• 通讯作者: Schmidt WN

Heme and HO-1 Inhibition of HCV, HBV, and HIV.

• DOI: 10.3389/fphar.2012.00129
• 发表时间: 2012
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Schmidt WN;Mathahs MM;Zhu Z
• 通讯作者: Zhu Z

Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity.

• DOI: 10.1002/prp2.882
• 发表时间: 2021-12
• 期刊: Pharmacology research & perspectives
• 影响因子: 2.6
• 作者: Zhu Z;Tran H;Mathahs MM;Fink BD;Albert JA;Moninger TO;Meier JL;Li M;Schmidt WN
• 通讯作者: Schmidt WN