lncRNA-1108扰乱内质网的非折叠蛋白反应对胃印戒细胞癌的作用机制研究

胃癌是我国死亡率第三的恶性肿瘤，其中胃印戒细胞癌比例高达30%。胃印戒细胞癌恶性度高，进展快，易转移，对目前化疗方案不敏感，发病和耐药机制不清，缺乏针对性分子治疗靶点，治疗决策十分受限。本课题组前期转录组测序发现lncRNA-1108在胃印戒细胞癌中显著上调，与淋巴结转移正相关。进一步发现：①lncRNA-1108可促进胃印戒细胞癌恶性表型的形成、抵抗5-FU诱导的细胞凋亡；②lncRNA-1108能结合并上调非折叠蛋白反应关键调控因子ATF6、SKP1；③外泌体中可检测到lncRNA-1108；④ATF6可与5-FU代谢限速酶DPD和TP的启动子区结合。本课题组拟解析lncRNA-1108通过非折叠蛋白反应诱导胃印戒细胞癌转移和耐药的分子机制；结合临床数据和PDX模型，探讨lncRNA-1108联合非折叠蛋白反应抑制剂在胃印戒细胞癌中的作用机理，为胃印戒细胞癌的诊治提供新思路和科学依据。

Gastric cancer is the third most common malignant tumor in China. The proportion of gastric signet ring cell carcinoma (GSRCC) is over 30%. The characters of GSRCC are high malignancy, rapid progress, easy to metastasis, and insensitive to current chemotherapy regimens. The treatment of GSRCC is very limited with lacking targeted molecular therapy targets due to its unclear mechanisms of pathogenesis and drug resistance. Our group discovered that lncRNA-1108 was significantly upregulated and positively correlated with lymph node metastasis in GSRCC through transcriptome sequencing. It was further found that: ① lncRNA-1108 can promote the formation of malignant phenotype of GSRCC and resist 5-FU induced apoptosis; ② lncRNA-1108 can bind and up-regulate ATF6 and SKP1 which are key regulators of Unfolded Protein Response; ③ LncRNA-1108 can be detected in exosomes; ④ ChIP indicates that ATF6 can bind to the DPD and TP promoter regions of 5-FU metabolic rate-limiting enzymes. This project intends to analyze the molecular mechanism of lncRNA-1108 inducing metastasis and drug resistance of GSRCC through unfolded protein response, and to reveal a new mechanism for the etiology of GSRCC. Combined with clinical data and PDX model, our group explore the effect of lncRNA-1108 with unfolded protein response inhibitors in GSRCC and provide new ideas for the diagnosis and treatment of GSRCC.