ABCC1调控区域遗传变异与非小细胞肺癌预后的关联及其促进肺癌恶性进展的机制研究

Lung cancer is the leading cause of cancer-related mortality worldwide and characterized by individual variations. More recently, molecular subtyping is now routinely used in management of patients with lung cancer, but there have been so for very few reported about molecular markers that are able to evaluate prognosis of lung cancer. Selection and identification of molecular markers will lead to rational prioritization of effective targeted therapies, providing clinical benefits for patients with lung cancer. In our preliminary study, we used Web-based search strategy and SNPs in genome-wide SNP data, we found the most overlapped SNP rs562009107 A＞G in ABCC1 was inversely associated with the risk of lung cancer. As a result, the expression of ABCC1 was significantly higher in lung cancer tissues with distant metastasis than that in lung cancer tissues without distant metastasis. Although some studies reflect relations between ABCC1 expression and clinical (multi)drug resistance, the roles of ABCC1 in promoting cancer cell metastasis remain unknown, and mechanisms behind their up-regulation in tumor tissue are also not entirely understood. Based on the previous study, we are going to carry out the work as the following: First, verify the changes of the expression of ABCC1 are results from the above SNP’s modification to the binding between the transcription factor and the promoter based on the EMSA. Second, evaluate the biological function of the gene ABCC1 in the development and metastasis of lung cancer. Eventually, the study will illuminate the relations and possible mechanisms between ABCC1 SNPs and lung cancer prognosis and metastasis, provide theoretical evidences to identify ABCC1 as a marker for early detection of lung cancer and provide innovative ideas for the clinical individual treatments on patients with lung cancer.

肺癌治疗已进入分子分型为基础的个体化治疗时代。筛选新的标记物是分子分型治疗的关键。前期经文献检索和基于SNPs的全基因组关联分析筛查出一个SNP (rs562009107 in ABCC1)与非小细胞肺癌相关联。研究显示ABCC1在发生转移的癌组织中表达异常升高。ABCC1作为肿瘤耐药基因研究较多，然而其促进肿瘤转移的作用未见报道，其在肿瘤组织表达上调的机制也未明确。课题拟通过①人群大样本单纯病例研究明确rs562009107基因型改变与肺癌易感及预后的关系；②EMSA等方法验证rs562009107 A＞G通过改变转录因子Sp1与启动序列结合的能力，导致ABCC1表达量的变化；③从临床、细胞和动物模型三个层面对ABCC1促进肿瘤恶性进展的生物学功能开展研究。最终阐明rs562009107基因型和ABCC1表达与肺癌发展和预后的关联和生物学机制，为其成为肺癌个体化评估的分子标记物提供依据。

SNP rs562009107 是申请人团队借助数据库和文献检索平台筛选获得的人非小细胞肺癌相关SNPs，并利用基于SNPs的GWAS 策略进行大样本验证获取目的基因的基础上提出的，通过本研究证实，ABCC1启动子区域的遗传变异（rs562009107 A＞G) 可以促进Sp1与其结合，进而促进ABCC1转录活性，这可能是非小细胞肺癌中ABCC1表达失控的遗传学机制，即促使ABCC1在肺癌组织和细胞株中高表达。同时，本项目发现ABCC1高表达可以促进非小细胞肺癌的恶性转化，使得非小细胞肺癌细胞的增殖、侵袭和迁移能力增强，与SP1介导的信号通路相关；项目通过基于SNPs的GWAS策略进行大样本验证了位于 ABCC1上游的 SNP rs562009107 A>G 与肺癌较差的预后关联研究，从目前研究看，在360例有效检测标本中，rs562009107 的“A＞G”突变达到了69例，占比为19.17%。依托项目共发表SCI论文6篇，部分研究成果获得2020年中国发明协会发明创业奖一等奖、2017年黑龙江省科学技术奖二等奖和2019年黑龙江省科学技术奖二等奖，依托此课题培养博士1人，硕士研究生2人。