ROS代谢通路相关代谢酶表达及其基因遗传变异与胃癌耐药的关联研究及机制探讨

The balance between reactive oxygen species (ROS) generation and scavenging is crucial for maintaining cellular homeostatis. In order to survive oxidative stress, cancer cells may have acquired adaptive mechanisms in ROS scavenging systems, which affect the prognosis and chemotherapy efficacy. Our previous study showed that the functional single nucleotide polymorphism (SNP) in one of the ROS scavenging related antioxidant enzymes (SOD2 rs4880) was associated with poor prognosis in gastric cancer patients who had chemotherapy. This finding suggests that the genetic changes in ROS scavenging related genes may participate in the protective mechanisms when cancer cells are under oxidative stress, and promote gastric cancer chemoresistance and progression. In this project, we will carry out a systematic study on the associations of ROS related antioxidant enzymes' functional SNPs and gastric cancer prognosis and chemotherapy efficacy, in order to identify the critical enzymes and their SNPs which are significantly related with gastric cancer progression. Furthermore, these SNPs' effects on enzymes expression levels, activities and ROS levels will be investigated in another cohort of gastric cancer tissue to assess the associations between genotypes and phenotypes. Finally, the biologic functions of each critical enzymes' SNPs in gastric cancer chemoresistance and the underlying mechanisms will be studied in in vitro and in vivo experiments by using enzyme inhibitors and chemodrugs. This project aims to clarify the biological mechanisms of genetic changes in ROS related antioxidant enzymes in gastric cancer chemoresistance, and to provide important references on personalized chemotherapy and efficacy prediction.

ROS产生和清除的平衡对维持细胞内环境稳定具有重要作用，肿瘤细胞为适应高ROS环境常发生抗氧化系统改变，从而影响肿瘤化疗的疗效与预后。我们的前期研究显示ROS代谢通路中抗氧化酶功能性单核苷酸多态性（Single Nucleotide Polymorphism，SNP）位点SOD2 rs4880与胃癌患者化疗后预后不良有关，提示ROS相关基因遗传变异是肿瘤细胞适应氧化应激损伤的保护性机制之一，参与胃癌耐药和进展。本课题将在此基础上，系统性筛选ROS代谢通路抗氧化酶类及其相关基因功能性SNPs，分析并获得抗氧化酶表达水平及功能性SNPs单独或联合与胃癌耐药和预后之间关系的证据；继而通过观察相关基因表达和细胞ROS水平，综合评价基因型-表型相互关系；并联合酶抑制剂和化疗药物，对阳性关联SNP及相关抗氧化酶进行生物学研究。最终阐明其影响胃癌耐药和预后的机制，为胃癌个性化化疗及疗效预测提供重要参考。