LncRNA-422基因遗传变异与结直肠癌发生发展的机制研究

Long non-coding RNAs (lncRNAs) are a set of functional RNAs with longer than 200 nucleotides and no protein-coding capability, which have been reported involved in tumorigenesis. It has been demonstrated that lncRNAs genetic variations, mainly referring to SNPs, could affect lncRNAs expression and its transcriptional regulation. In our previous study, we have performed a global lncRNAs expression profile on colorectal cancer tissues, and identified lncRNA-422 as a candidate lncRNA for its association with colorectal cancer development and progression; however, its biological mechanisms have not been yet clear. In this study, we plan to conduct a two-stage case-control study to evaluate the association between lncRNA-422 SNPs and colorectal cancer risk and outcome. We will use a series of cellular and molecular biology methods to explore the effect of genetic variants on lncRNA-422 expression and molecular mechanisms, so as to further elucidate the biological mechanisms of lncRNA-422 during colorectal cancer development and progress. The project will provide reference for the early protection and clinical prognosis evaluation of colorectal cancer.

长链非编码RNA（lncRNA）是一类长度超过200个核苷酸，且生物学功能丰富的一类非编码RNA，参与肿瘤的发生发展。目前认为lncRNA的遗传变异（以单核苷酸多态性SNPs为主）可影响lncRNA的表达及其转录调控。本课题组前期通过全基因组lncRNAs芯片表达谱筛选，发现在结直肠癌组织中差异表达的lncRNA-422与结直肠癌的发生密切相关，但其机制尚不完全清楚。本项目拟基于前期实验结果和最新研究进展，针对lncRNA-422的遗传变异，采用两阶段的病例-对照研究，探讨lncRNA-422的SNPs与结直肠癌发病风险和临床表型的关联性；并综合采用一系列细胞分子生物学方法，研究遗传变异对lncRNA-422表达和分子调控的作用，进一步阐明lncRNA-422在结直肠癌发生发展过程中的生物学机制。该项目的实施可为今后实现结直肠癌早期预防和预后判断提供参考。

结直肠癌是世界上最常见的消化道恶性肿瘤之一，其发病率和死亡率在全球范围内排名第三和第二。结直肠癌的发生发展及预后是环境因素、遗传因素和表观遗传等多方面综合作用的结果。本课题组前期通过表达谱芯片筛选出lncRNA-422与结直肠癌的发生密切相关。且长链非编码 RNA生物学功能丰富，可参与结直肠癌的发生发展。因此，本项目基于前期研究基础提出科研假说：lncRNA-422及其遗传变异参与结直肠癌的发生发展的功能和机制。采用人群研究探讨遗传变异和结直肠癌易感的关联性；利用RNA pull-down、质谱、RIP等方法深入探讨其参与调控SFPQ蛋白的生物学机制；同时基于EdU、流式细胞术、免疫组化和免疫荧光等验证lncRNA-422、SFPQ及二者之间相互调控的细胞表型和动物模型；利用TCGA、GEO等公共数据库及本实验收集的结直肠癌与癌旁组织，验证lncRNA-422与临床的相关性，以及与SFPQ的调控作用。该研究较好的实现人群研究、功能鉴定、动物实验及组织学验证等有机结合，以临床研究为导向，为揭示表观遗传参与结直肠癌发展的功能和机制研究提供重要的生物学基础，也为今后结直肠癌个体化治疗及药物研发等提供一定的参考价值。