缺氧信号介导卡波氏肉瘤病毒致病作用及机制研究

Kaposi's sarcoma (KS) is the most common malignant vascular skin tumor in the AIDS and organ transplant patients, which caused by Kaposi's sarcoma-associated herpes virus (KSHV) infection. Many clinical data has shown that KSHV has persistent infection life cycle,and that KS commonly exists intratumoral hypoxia which readily leads to tumor cell metastasis and anti-cancer treatment. The co-carcinogenic effect of hypoxia signal with KSHV infection is currently hot topic. We and other colleagues have achieved some initial results in this field. However, how KSHV responds to hypoxic stress and regulates hypoxia-inducible factor HIF signaling pathway to achieve persistent infection and induce tumor formation is not fully understood. Based on our preliminary work, in this proposal we focuse onthe regulation of key nuclear antigen LANA encoded by KSHV in latency to further address the molecular mechanisms of how KSHV establishes and maintains latent infection by regulating hypoxia HIF signaling and responds to hypoxic stress for lytic reactivation in term of control of the infection cycle, and whetherthe different hypoxia signal interference target impairs the KSHV infected cells anti-apoptosis and proliferation as well astumor formation in vivo. The implementation of this project will contribute to establish a classical molecular model about how hypoxia signal and virus infection co-induced carcinogenesis, and to provide new targets and strategies for the diagnosis and treatment of KSHV associated cancers.

卡波氏肉瘤(KS)是一种艾滋病和器官移植患者中常见的恶性血管性皮肤肿瘤，由卡波氏肉瘤病毒(KSHV)感染引起。大量的临床数据表明，KSHV能持续感染宿主细胞，且KS瘤内常出现缺氧现象而造成肿瘤细胞的转移和抗治疗。缺氧信号与KSHV感染致病作用关系是目前国内外研究热点，我们课题组及同行已初步发现缺氧可影响KSHV生活周期。但是，对于KSHV怎样应答缺氧应激、调控缺氧诱导蛋白(HIF)信号，以达到持续感染并诱发肿瘤生成的机理尚未完全清楚。本课题拟在前期工作的基础上，以KSHV潜伏期主要核抗原LANA为研究对象，深入探讨KSHV利用缺氧HIF信号建立并维持潜伏感染和应答缺氧应激启动裂解复制调控的分子机制；同时明确缺氧信号不同靶点干预对KSHV感染细胞抗凋亡和增殖及体内肿瘤发生发展的影响。本项目的实施将有助于建立一个缺氧信号和病毒共致癌的典型分子机制模型，并为KSHV肿瘤诊治提供新的靶点和策略。

卡波氏肉瘤(KS)是一种艾滋病和器官移植患者中常见的恶性血管性皮肤肿瘤，由卡波氏肉瘤病毒(KSHV)感染引起的KS瘤内常出现缺氧现象而造成肿瘤细胞的转移和抗治疗。对于KSHV怎样应答缺氧应激、调控缺氧信号，以达到持续感染并诱发肿瘤生成的机理尚未完全清楚。经过四年研究,我们取得了如下进展: 1）解析了与应缺氧应激相关LANA结构域SIM（LANASIM）的特异互作靶蛋白网络及其关键靶蛋白；2）阐明了不同类型细胞中LANASIM与LANASOCS在调节缺氧信号通路中的相互关系，尤其发挥STUBL功能调控同一靶蛋白的潜在作用；3）明确了缺氧应激与化学试剂TPA/NaB诱导KSHV子病毒的产生机制及颗粒包装成分的差异；4）揭示了缺氧诱导KSHV子病毒促进原发感染早期病毒基因组快速复制、逃避宿主先天免疫、DNA损伤修复和克隆形成等潜伏建立维持的致瘤作用；5）发现了天然小分子Cambogin作为LANASIM–SUMO2靶向抑制剂对特异消除KSHV相关肿瘤生成的作用。我们的研究将有利于更好地理解KSHV病毒致癌机制,为抗KSHV相关肿瘤诊治提供了新的靶点和策略。