p53差异转录调控GPC1/miR-149-5p介导胃癌耐药新机制的研究

耐药是胃癌致死的重要原因。我们前期发现miR-149-5p靶向CXCR1；CXCR1促ERK和AKT磷酸化，介导胃癌耐药。前期蛋白质组学鉴定出CXCR1下游一些新靶点，可能直接或间接调控细胞周期、线粒体和FASL/FAS凋亡通路。生物信息学显示p53在miR-149-5p宿主基因GPC1启动子区有潜在结合位点；突变型p53介导肿瘤耐药。由此我们提出科学假说：野生型和突变型p53差异转录GPC1和miR-149-5p，一方面通过CXCR1促进ERK和FAK/AKT通路，上调hnRNPK、Hsp27和Sorcin，介导线粒体和FASL/FAS凋亡通路crosstalk，导致细胞逃避化疗诱导的凋亡，另一方面GPC1和CXCR1通过crosstalk促进细胞周期；最终导致耐药。拟从细胞-动物-分子-临床四个层面验证假说。项目的完成将阐明p53通过GPC1/miR-149-5p介导胃癌耐药的新机制。

Chemotherapy resistance is the important reason for gastric cancer(GC) related death. We previously found that miR-149-5p targets CXCR1, and CXCR1 promotes ERK and AKT phosphorylation and mediates chemotherapy resistance in GC. With the help of proteomics and mass spectrometry experiments, we identified some CXCR1 silencing related new target proteins (hnRNPK, HSP27 and sorcin),which directly or indirectly mediated cell cycle, mitochondrial and FASL /FAS apoptosis pathway. Bioinformatics analysis showed that there is one potential p53 binding domain in the promoter region of host gene GPC1 of miR-149-5p; and mutant type p53 regulates chemotherapy resistance in tumors. Therefore, on the above basis, in this project we put forward the following scientific hypotheses: the wild type and mutant type p53 differently regulated transcription of GPC1 and miR-149-5p, and p53/GPC1/miR-149-5p-CXCR1 regulating axes, on the one hand, mediates mitochondria and FASL/FAS apoptosis pathway crosstalk by CXCR1 promoting ERK and FAK/AKT pathway, and then prompting hnRNPK, HSP27 and sorcin expression, which causes the cells to evade apoptosis induced by chemotherapy; On the other hand, GPC1 and CXCR1 promote cell cycle through crosstalk, eventually leading to chemotherapy resistance in GC. We intend to verify the above scientific hypothesis from four levels of cells - animal models - molecules - clinical samples. The project will elucidate the new molecular mechanism of p53 mediating chemotherapy resistance through GPC1/miR-149-5p.