MiRNA/lncRNA/circRNA/tRF调控BIRC5基因异常表达抑制胃癌细胞凋亡及促进耐药的分子机制研究

胃癌是发病率和死亡率均居前列的恶性肿瘤，发现新的标志物及治疗靶点，意义重大。申请者在发现胃癌中异常高表达的BIRC5可抑制胃癌细胞凋亡及促进耐药的基础上，结合芯片、生物信息学及实验验证，推测定位于细胞核的linc-01973可作为elncRNA促进细胞核内BIRC5转录合成；当BIRC5 mRNA转运到细胞质后，circRNA-405338能够作为ceRNA竞争性结合miR-596、miR-3620-3p，保护BIRC5不受miRNAs的降解作用，从而上调BIRC5表达；同时，胃癌中低表达的tRF-1041进一步导致了其靶基因BIRC5异常高表达。在此基础上，本项目拟深入探讨miRNA, circRNA, lncRNA及tRF导致胃癌细胞中BIRC5异常高表达的分子机制。进一步干预各调控环节，下调胃癌细胞内源性BIRC5表达，促进胃癌细胞凋亡及降低耐药，将可能为胃癌的临床治疗提供新的靶点。

Gastric cancer is with higher morbidity and mortality among the cancers and it’s of great significance to find novel biomarkers for early diagnosis and new molecular targets for gastric cancer. In our previous work, we have already found that the aberrant up-regulation of BIRC5 demonstrated in gastric cancer tissues inhibits the apoptosis and promotes the drug resistance of gastric cancer cells. On the basis of this finding and subsequent confirmation via microarray, bioinformatics analysis and experiments, we presume that linc-01973, which is located in the nucleus, can act as elncRNA to promote the transcription of BIRC5; After the transportation of BIRC5 mRNA from nucleus to cytoplasm, circRNA-405338 can act as ceRNA and competitively bind with miR-596、miR-3620-3p to prevent the degradation of BIRC5, up-regulating the expression of BIRC5; Meanwhile, the down-regulated tRF-1041 further lead to the aberrant up-regulation of BIRC5, a target of tRF-1041. On this foundation, we aim to investigate the molecular mechanism of miRNA, circRNA, lncRNA, and tRF on leading to the aberrant up-regulation of BIRC5 in gastric cancer cells. Further interfering the regulatory processes can reduce the expression of endogenous BIRC5 in gastric cancer cells, and then promotes the apoptosis and reduces the drug resistance of gastric cancer cells. Thus, we may provide new targets for the clinical treatment of gastric cancer.