YAP介导的GPCRs信号相关异常分子事件在口腔鳞癌发生发展中的作用及其潜在临床意义研究

YAP, a transcriptional co-activator, which regulates organ size, has been found aberrant activated in multi cancers as a pre-oncogene. G-protein-coupled receptors (GPCRs) represent by far the largest family of cell-surface molecules involved in signal transmission, accounting for >2% of the total genes encoded by the human genome. Emerging experimental and clinical data indicatethat GPCRs have a crucial but often not fully appreciated role in cancer progression and metastasis. Previous studies of our group partly found GNAQ oncogene can trigger YAP aberrant activation, and uncovered G-protein oncogenic signaling regulating YAP activation new mechanism. Based on these important findings, in this proposal we will investigate YAP activation study from aberrant GPCRs related molecular events in oral cancer. First, we will confirm YAP aberrant activation in oral cancer. Then through Oncomine data fishing and analysis, binding YAP signature genes expression levels, to find YAP activation associated GPCRs related aberrant molecular events and confirm by in vitro experiment. After all, focus on functions study of YAP over-activation by GPCRs related aberrant molecular events to uncover its contribution for oral cancer genesis and metastasis. This study will inspire a new phase of therapeutics for oral cancer, one of the most common cancers in China, and shed light on the basic principles of cancer initiation and development.

YAP是新近受关注的转录辅助激活因子，被认为是一种重要的原癌基因。G蛋白偶联受体(GPCRs)是细胞表面最重要的信号传输家族之一，是重要的抗癌药物靶标。申请人发现了Gαq（一种直接作用于GPCR的分子）异常信号调控YAP活化的新机制，即可以不依据于传统的Hippo信号通路；但是否不同GPCRs具有相似功能，以及这种新的信号传导机制在不同肿瘤中是否是一种普遍规律，都须进一步阐明。为此，本课题以我国高发的口腔鳞癌(OSCC)为研究模型，研究YAP在OSCC癌变、转移等阶段的表达变化及临床相关性；明确不同GPCRs异常分子事件对YAP活化的调控作用及途径，以及关键的GPCRs；阐明YAP活化在介导GPCRs异常分子事件调控OSCC细胞增殖与转移中的作用，明确其作为OSCC潜在诊疗靶标的价值。成果不仅将进一步揭示YAP介导的GPCRs异常信号在人类恶性肿瘤中的作用，也可为OSCC的诊疗提供新的思路