雄激素受体调控miR-125b及lncRNA影响胃癌进展与预后的分子机制与应用研究

胃癌发病率和死亡率存在性别差异,并受激素和激素受体调控,但机制不明。申请人课题组前期构建了大型胃癌队列,证实雄激素受体（AR）与胃癌预后密切相关,在女性病人中尤为显著。同时对90例胃癌全基因组mRNA-miRNA表达谱芯片整合分析,富集到以miR-125b作为关键基因的与预后相关的miRNA调控网络亚型,并与凋亡通路相关。生信分析及chip-seq等结果提示AR结合miR-125b启动子区及其上下游及远端非编码区（富含lncRNA）。本研究将进一步通过机制和功能实验,阐明AR对miR-125b及相关lncRNA的调控作用及促进胃癌的恶性进展,导致不良预后的分子机制。同时利用ChIA-PET、ATAC-seq等联用从三维基因组层面绘制AR调控的全景图谱并鉴定其作用的精细模式。通过构建胃癌类器官和PDX等体内外模型,评估AR拮抗剂对胃癌的抑制作用,为胃癌治疗提供新靶标和理论及实践基础。

There are gender differences in the incidence and mortality of gastric cancer, which are regulated by hormones and hormone receptors, but the mechanism is unknown. A large cohort of gastric cancer was constructed by the applicant's research group, and it was confirmed that androgen receptor (AR) was closely related to the prognosis of gastric cancer, especially in female patients. At the same time, the integrated analysis of the whole genome mRNA-miRNA expression profile microarray of 90 cases of gastric cancer showed that the subtypes of miRNA regulatory network related to prognosis with miR-125b as the key gene were enriched, and were related to apoptosis pathway. The results of bioinformatics analysis and chip-seq suggest that AR binds to the promoter region of miR-125b and its upstream, downstream and distal non-coding regions (rich in lncRNA). This study will further clarify the molecular mechanism of AR on the regulation of miR-125b and related lncRNA and promote the malignant progression of gastric cancer and lead to poor prognosis through mechanism and functional experiments. At the same time, the panoramic map of AR regulation was drawn from the three-dimensional genome level by CHIA-PET and ATAC-seq, and the fine pattern of its action was identified. The inhibitory effect of AR antagonists on gastric cancer was evaluated by constructing gastric cancer organoid and PDX models in vivo and in vitro, so as to provide a new target and theoretical and practical basis for the treatment of gastric cancer.