激活HERV-K编码原癌蛋白NP9在卡波西肉瘤发生发展中作用

导致艾滋病人死亡的病因常见于各种病原体感染所致并发症，包括卡波西肉瘤疱疹病毒（KSHV）引起的卡波西肉瘤（KS）,目前KSHV致癌的分子机制仍不明确且针对AIDS-KS无特效疗法。本课题组前期研究发现KSHV感染在体内体外激活人内源性逆转录病毒HERV-K编码原癌蛋白NP9表达，而抑制NP9表达显著削弱KSHV感染诱导内皮细胞的恶性行为。本研究拟以KSHV/KS为病毒致癌模型，通过构建缺失突变体研究KSHV编码主要潜伏蛋白LANA调控NP9表达的分子机制；研究EMMPRIN-ADAMTS1/9-VEGF信号通路在NP9诱导内皮细胞恶性行为中作用；通过已建立的KS裸鼠模型来探讨纳米颗粒结合RNA干扰NP9表达的抗KS肿瘤体内疗效。本研究将为阐明激活NP9原癌蛋白在致癌病毒相关肿瘤中作用，改善AIDS-KS肿瘤治疗效果提供有价值实验数据。

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS), which represents one of the major complications causing AIDS patients death. However, currently conventional chemotherapy has poor effect on AIDS-KS, which requires deeply understanding how the virus interacts with host factors and identifying novel “drug-target”. Our preliminary data indicated that HERV-K encoded oncoprotein NP9 was transctivated in vitro and in vivo, contributing to KSHV-induced endothelial cell malignant behaviors. To further investigate its role in AIDS-KS development, this study will include: 1) determine the mechanisms through which KSHV-encoded latent protein LANA activating NP9; 2) determine the role of EMMPRIN-ADAMTS1/9-VEGF signaling axis in NP9-induced endothelial cell malignant behaviors; 3) test whether targeting NP9 by nano-particle combined with RNAi technology, will suppress tumor growth in a KS xenograft nude mice model. We hope our data will lead to innovative mechanistic insights for the role of HERV-K NP9 transactivation in KS development and provide the framework for development of targeting NP9 therapy and implementation of clinical trials for AIDS-KS patients in future.