COL4A3-AKT通路在慢性阻塞性肺病促进肺癌进展的作用研究

Chronic obstructive pulmonary disease (COPD) and lung cancer are both devastating pulmonary diseases, and impose a major disease mortality burden on healthcare system worldwide. Lung cancer arising in COPD is more aggressive and associated with worse prognosis compared to lung cancer without COPD. Our previous clinical researches revealed that more than 50% lung cancer patients had COPD, and COPD conferred 1.23-fold increased risk of lung cancer death. However, the mechanistic links are poorly understood and there is no biologic target for both prevention and treatment of lung cancer with COPD. In the preliminary study, we have retrieved 304 candidate genes and 8,409 single nucleotide polymorphisms (SNPs) that have been reported to be involved in COPD and/or lung cancer development through a web-based search strategy. In addition, the candidate genes and SNPs are further validated in a large cohort via a genome-wide association analysis. Finally, only 1 candidate gene, COL4A3, passed the threshold of statistical significant difference, which is likely to be involved in the process of COPD-associated lung cancer development. In this study, we aim to further reveal the biologic function of gene COL4A3 at the levels of clinical tissue samples, cell culture, as well as animal models, and to identify whether COL4A3 promotes lung cancer invasion and angiogenesis by activating AKT signal pathway. Increasing understanding of the relationship between COPD and lung cancer will allow the development of better cancer preventive and therapeutic strategies and ultimately will improve the outcomes of this patient population.

慢性阻塞性肺病（COPD）和肺癌均是肺部致命性疾病，对全球卫生体系造成了严重的疾病死亡负担。起源于COPD的肺癌往往更具侵袭性且预后更差。我们前期临床研究发现，50%以上的肺癌患者合并COPD，而COPD将增加1.23倍的肺癌死亡风险；但其具体机制尚不清楚，临床也缺乏有效的干预靶点。在前期研究工作中，通过数据库检索平台，我们共发现304个候选基因和8409个单核苷酸多态性（SNP）位点与COPD和/或肺癌相关。并通过基于SNP的全基因组关联分析技术对上述候选基因和SNP进行大样本验证，最终筛查出1个候选基因COL4A3可能参与了COPD促进肺癌进展的过程。结合既往文献，本研究拟从临床样本、细胞水平和动物模型三个层面，对COL4A3的生物学功能进行研究，阐明COL4A3是否调控AKT信号通路促进肺癌侵袭和肿瘤新生血管生成。研究结果以期为COPD患者肺癌的预防和治疗提供新线索。

慢性阻塞性肺病（COPD）和肺癌均是肺部致命性疾病，对全球造成了严重的疾病负担。据统计，约50%肺癌患者合并COPD，而COPD将影响约27%肺癌治疗模式。因此，了解COPD相关性肺癌（COPD-associated lung cancer）的发病机制具有重要临床意义。申请人利用遗传流行病学方法，采用基于单核苷酸多态性（SNP）的全基因组关联（GWA）策略，对肺癌和COPD相关基因进行了全方位筛查。同时，对临床标本根据肺功能进行分组，对单纯肺癌与COPD相关性肺癌的SNP分析发现，COPD相关性肺癌存在独特的遗传易感性。临床样本发现COPD相关性肺癌COL4A3表达水平升高。进一步对候选基因COL4A3生物学功能验证发现，敲减COL4A3表达后，肺癌细胞的增殖、凋亡、迁移和侵袭能力均显著下降，并且小管生成实验班发现人脐静脉内皮细胞的小管生成能力降低。过表达COL4A3后AKT及其磷酸化水平，以及EMT相关分子如ZEB1、Vimentin等均显著上调。小鼠转移瘤动物模型证实尾静脉注射COL4A3过表达的肺癌细胞株后，肺转移瘤数目明显增多。临床研究发现，COPD是肺癌预后的独立危险因素（HR, 1.22; 95%CI, 1.18-1.27）。并且，COPD肺气肿表型与肺癌预后相关，包括远期生存、生活质量和肺功能恢复情况。针对COPD相关性肺癌的囊腔类型，率先提出分型：薄壁型、厚壁型、壁结节型和混合型，并且经临床变量倾向评分平衡后，该分型与患者预后相关，3年无复发生存率分别为100%、84%、77%和83%。通过上述全基因组筛查、基因生物学功能验证和临床数据分析，系统阐明了COPD相关性肺癌可能的发生机制和临床预后，为COPD相关性肺癌的防治和规范性诊疗提供一定的理论基础。