肺癌是癌症患者致死第一原因。STAT3信号通路在非小细胞肺癌发生过程中频繁发生异常性激活，然而机理不清。GPRC5A是新发现的肺肿瘤抑制基因。Gprc5a-敲除小鼠会产生自发性肺腺癌。我们发现，Gprc5a的缺失会导致小鼠肺气道上皮细胞中STAT3信号异常性激活。这提示，Gprc5a对STAT3信号通路有抑制作用。我们还发现，GPRC5A可与STAT3上游调控分子EGFR和IL-6R的Co-receptor gp130形成复合物。这暗示，GPRC5A可能通过调控这类分子而起作用。我们假设，GPRC5A的抑制或缺失是导致肺癌早期STAT3信号通路异常激活，也是恶性转化的重要机制。本课题将通过用IL-6小鼠与Gprc5a敲除小鼠杂交，研究STAT3信号通路在肺癌发生中的作用。同时将进行多层次的系统研究，确立两者之间的相互调控关系。本研究将对肺癌早期诊断、早期预防、靶向治疗有着重要意义。

Lung cancer is the leading cause of cancer death worldwide. STAT3 is a key oncogene that plays a critical role in the early stages of lung carcinogenesis. However, the mechanism of STAT3 dysregulation in lung carcinogenesis is unclear. GPRC5A is a newly identified lung tumor suppressor gene. Gprc5a-knockout (ko) mice develop spontaneous lung adenocarcinoma. Recently, we found that STAT3 signaling pathway was aberrantly activated in Gprc5a-ko mouse bronchioalveolar epithelial cells in comparison with that in wild type cells. Consistently, over-expression of exogenous GPRC5A inhibits STAT3 signaling. This observation suggests that, Gprc5a functions as a negative regulator of STAT3 signaling. Moreover, we found that GPRC5A formed complexes with upstream regulator gp130, a co-receptor for IL-6R and IifR, implying that GPRC5A may act via interaction with these molecules. We hypothesize that repression or deletion of GPRC5A is an important mechanism of dysregulation of STAT3 for lung carcinogenesis. The proposed project will study the effect of IL-6 blockage on lung tumorigenesis in Gprc5a-ko/Il-IL-6-ko mice. The proposed study is important for revealing a novel molecular mechanism of STAT3 dysregulation for lung carcinogenesis, and for early diagnosis, prevention, and therapy against lung cancer.