非可控炎症微环境在肺癌发生和转移过程中的不同作用及干预策略

肺癌是致死率最高的肿瘤，其发生和转移不仅取决于遗传突变，也取决于肿瘤微环境。非可控炎症微环境起到重要的促进作用，然而机制不清。揭示这一机理需要能模拟人疾病特征的动物模型，GPRC5A是新发现的肺癌抑制基因，Gprc5a敲除(ko)小鼠肺组织不仅对炎症信号易感，也对肺癌发生和转移易感，而且其相应病理特征与人十分相似，包括NF-kB和IL-6/STAT3信号异常性激活。通过杂交将Gprc5a-ko小鼠肺组织NF-kB和IL-6信号分别阻断，我们意外发现NF-kB和IL-6信号尽管都参与炎症微环境，但在肺癌发生和转移过程中的作用却完全不同：NF-kB信号抑制肺癌发生，对转移没有作用；IL-6信号，抑制肺癌转移，对肺癌发生没有影响。本研究将以Gprc5a-ko小鼠为基础，对炎症微环境中NF-kB和IL-6/STAT3信号在肺癌发生和转移中的不同作用和机理进行系统研究，为肺癌的治疗方案提供新思路。

Lung cancer and lung metastasis are the leading cause of cancer-related death.Cancer development is not only depends on the genetic mutations within cancer cell itself, but also depends on the tumor microenvironment. Many evidences show that chronic inflammatory microenvironment plays a critical role in the process. However, the mechanism remains elusive. Mechanistic study needs an animal model that can resemble the pathological process and characteristics of human disease. GPRC5A is a newly identified lung tumor suppressor gene. Gprc5a knockout (KO) mice are not only susceptible to lung tumorigenesis, but also to lung metastasis. Importantly, the pathological features are very similar to those of human lung cancer and metastasis, including chronic inflammation, aberrant activation of NF-kB and IL-6/STAT3 signaling pathwayin lung tissue. By cross-breeding with mice of blocked NF-kB or IL-6 pathway, we unexpectedlyfound that although both pathways are involved in promotion of inflammation, their roles and mechanisms in lung tumorigenesis and metastasis are completely different, which has great implication in designing distinctive therapeutic protocol for lung cancer and metastasis, respectively.In this proposal, we intend to use Gprc5a-ko mouse model to study the roles and mechanisms of NF-kB and STAT3 signalingfrom inflammatory microenvironment in lung cancer occurrence and metastasis, we intend to establish distinctive strategies of prevention and therapy for lung tumorigenesis and metastasis by targeting tumor microenvironment.