GPRC5A基因杂合性缺失在肺癌发生中的作用机理和意义

肺癌是致死人数最多的癌症。肺癌的发生与癌基因驱动突变紧密相关。癌基因（如EGFR）驱动突变的鉴定对肺癌的靶向治疗至关重要。GPRC5A是新发现的肺肿瘤抑制基因，其在人肺癌组织中常被抑制。Gprc5a敲除小鼠会产生自发性肺肿瘤，许多病理变化与人肺癌的十分相似。我们假设，人肺癌中会发生GPRC5A基因杂合性缺失；该基因的缺失会予肺癌细胞以某种选择压力，使得其选择某类遗传突变或癌信号通路。本研究方案集中三个方面：首先，鉴定人肺癌组织中是否有GPRC5A基因杂合性缺失？发生频率是多少？其次，利用Gprc5a-ko小鼠肺癌动物模型，筛选Gprc5a基因缺失背景下肺癌细胞中的驱动突变癌基因，并检验人肺癌中是否有类似的遗传突变。最后，在体外重建这些突变体，分析其生化活性及生物学功能的改变。总之，我们欲利用Gprc5a敲除小鼠肺癌模型，揭示人肺癌中尚未探明的新机理，为肺癌的靶向治疗提供新靶标。

Lung cancer is the leading cause of cancer deaths. Lung carcinogenesis is associated with oncogenic driver mutantions, such as those on EGFR and K-Ras. Identification of oncogenic driver mutations is critically important for cancer therapy. There are still about half of lung cancer without identified driver mutations. GPRC5A is a newly identified lung tumor suppressor gene. GPRC5A is frequently repressed in human lung cancer. Gprc5a-knockout (ko) mice develop spontaneous lung tumor, which resembles the pathological features of human lung cancer. We hypothesize that loss of heterozygosity (LOH) of GPRC5A gene is frequent occurred in human lung cancer; and LOH of GPRC5A would confer a selection pressure for certain types of genetic mutations or pathways during lung carcinogenesis. In this research proposal, we are to study three specific aims and answer related questions: First, whether LOH of GPRC5A is occurred in human lung cancer? What is the frequency? Secondly, whether is there a common genetic or epigenetic pathway shared by Gprc5a-ko mouse lung cancer cells and human lung cancer (GPRC5A deficient) cells? Finally, by reconstitution and in vitro characterization of the newly identified oncogenic mutants, whether we could find the novel biochemical activities and biological pathways related to carcinogenesis in these lung cancer cells. Taken together, the proposed study will not only reveal new genetic mutations and reveal a novel mechanism of lung cancer, but also provide a novel strategy for targeted therapy of lung cancer.