甲羟戊酸通路调控分子RHOQ决定溶瘤病毒M1肿瘤靶向性的作用及机制研究

溶瘤病毒疗法是一种新兴的利用可复制病毒进行靶向抗肿瘤治疗的策略，具有低毒、高效等优点。本项目前期工作第一次鉴定甲病毒M1为新型溶瘤病毒，对多种肿瘤具出良好的抗肿瘤活性（PNAS，2014和Mol Ther,2016）。然而，我们观察到不同肿瘤对M1病毒的敏感性不一致，引起这种差异的分子机制尚未明确。近期，通过对M1病毒感染的肿瘤细胞转录组芯片分析和后续的siRNA筛选，我们鉴定甲羟戊酸/蛋白法尼基化通路下游的RHOQ具有抗病毒作用，进一步检测发现RHOQ在M1病毒敏感的肿瘤中缺失表达。这些结果提示RHOQ分子作为M1病毒精准治疗的分子标记的潜能。基于此，本项目拟进一步在细胞株及临床组织中确证RHOQ决定溶瘤病毒M1肿瘤靶向性的作用，构建稳定表达细胞株探索RHOQ的抗病毒分子机制。本研究的完成，有望为溶瘤病毒M1的精准治疗提供分子标志，并将阐明甲羟戊酸通路调控的抗病毒因子RHOQ的作用机制。

Oncolytic virus is emerging as a new targeting anti-tumor strategy, with advantages of safety and efficiency. Our team had been firstly identified alphavirus M1 as an oncolytic virus, which is able to kill many types of tumor. (Cell Cycle，PNAS and Mol Ther). However, our data shows that tumor cells represent different sensitivity to M1 virus treatment, and the related mechanism is not clear. Recently, by analyzing the transcriptome chip data of M1 virus infected cancer cells and then exploiting siRNA screening technique, we find out that RHOQ, a factor in the downstream of mevalonate-farnesylation pathway, is an antiviral factor, and its expression is deleted in M1 virus-sensitive cancer cells, which indicates that RHOQ is potential as a mark for M1 oncolytic precision therapy. Basing on these data, this project is planning to confirm the role of RHOQ in mediating tumor-targeting of M1 virus with more cell lines and clinical tissue samples, and to explore the anti-viral mechanism of RHOQ in over-expressing and knock-out cell line models. The finish of our work would provide a new mark for M1 oncolytic therapy, and the antiviral mechanism of mevalonate-regulated factor RHOQ would be clearly explained.