长非编码RNA ANRIL SNPs与胃癌氟尿嘧啶类药物敏感性关联研究及其机制探讨

It is of great needs to understand the mechanisms of fluoropyrimidine resistance and develop clinical strategies against this resistance in gastric cancer. lncRNA SNPs are closely associated with tumorigenesis, but its role in the chemoresistance is unclear. Our previous study has found that lncRNA ANRIL was involved in the development of gastric cancer; furthermore, its SNP rs3217992 could affect ANRIL expression levels and associated with the chemotherapeutic response and prognosis of gastric cancer. Therefore, we suggest that ANRIL associated SNPs may affect its expression, biological functions and its downstream chemoresistance related targets expression, which involve in fluorouracil resistance in gastric cancer. The present study intents to screen out chemoresistance related ANRIL SNPs and investigate their effects in regulation of ANRIL expression, biological functions and their associations with gastric cancer chemoresisance and prognosis; then demonstrate these effects in the in vitro and in vivo experiments; finally clarify the mechanisms of these regulations through a series of molecular biology experiments (such as ChIP and RIP, etc.). Our study would provide important experimental evidence for personalized therapy for gastric cancer.

胃癌氟尿嘧啶类药物耐药机制和临床应对策略是急需解决的问题。lncRNA SNPs与肿瘤的发生密切相关，但在肿瘤耐药中的作用尚不清楚。我们前期研究发现：lncRNA ANRIL参与胃癌的发展，其SNP rs3217992不同基因型影响其表达水平并与胃癌化疗疗效和预后相关。由此我们假设：ANRIL的SNPs影响其表达水平及生物学功能、调控其下游耐药相关基因，参与胃癌对氟尿嘧啶类药物的耐药。本课题旨在：系统筛选ANRIL SNPs，分析并获得ANRIL SNPs影响其表达水平和生物学功能及SNPs单独或联合与胃癌耐药和预后之间关系的证据；继而从离体水平揭示ANRIL SNPs对胃癌耐药细胞生物学功能的影响，并从整体水平加以验证；通过一系列分子生物学实验（如ChIP和RIP等）最终阐明ANRIL SNPs通过影响其表达和绑定PRC2调控胃癌耐药相关基因的可能机制。为胃癌个性化化疗提供重要实验依据。

胃癌氟尿嘧啶类药物耐药机制和临床应对策略是急需解决的问题。本研究实时跟踪胃癌氟尿嘧啶类药物耐药相关研究最新动态，不断优化方案，始终保持在国内领先水平。1、本研究对300例胃癌患者的长链非编码RNA ANRIL rs3217992进行基因分型，发现不同的基因型和胃癌肿瘤的大小、胃癌组织发生的部位、以及氟尿嘧啶的疗效有关。2、对胃癌患者的长链非编码RNA ANRIL的基因型和胃癌的预后进行分析后发现，GG基因型的患者的中位生存时间短于GA/AA基因型的患者，其差异具有统计学意义。3、300例胃癌患者预后经过多元回归分析，显示长链非编码RNA ANRIL rs3217992的不同基因型是接受氟尿嘧啶患者预后分析的独立预后因素（P=0.006）。4、随着长链非编码RNA ANRIL的敲低，两种耐药细胞对氟尿嘧啶的敏感性提高分别为1.9及1.74倍。同时发现，敲低长链非编码RNA ANRIL后mTOR蛋白水平随着长链非编码RNA ANRIL的敲低而下降。5、进一步的机制研究发现，显示长链非编码RNA ANRIL在耐药过程中可能具有抗凋亡活性。6、在本课题的实施过程，对其他的长链非编码RNA ANRIL的SNPs的不同基因型和胃癌预后以及氟尿嘧啶耐药之间的关系进行了探索性研究，尚未发现和胃癌预后和氟尿嘧啶耐药相关的长链非编码RNA ANRIL 的SNPs。通过以上研究阐明ANRIL SNPs调控胃癌耐药相关基因的可能机制，为胃癌个性化化疗提供重要实验依据。