遗传变异相关lncRNA GMAT1调控糖代谢重编程促进大肠癌发生的机制研究

Genome-wide association analysis has discovered more than 60 colorectal cancer (CRC) associated gene polymorphism sites (SNPs), however, the underlying mechanism remains unclear. Our previous study found that the SNP rs4925386 region might be an enhancer sequence, and the variant of this site could decrease the enhancer activity. The analysis of GTEx data showed that the genotypes of rs4925386 were significantly correlated with the upstream lncRNA GMAT1 expression, suggesting that SNP rs4925386 may downregulate GMAT1. Additionally, we found that the expression of GMAT1 was significantly upregulated in CRC tissue compared with normal adjacent tissue. The RNA-sequence and GSEA analysis further revealed that the glycolytic pathway was significantly down-regulated in GMAT1 knock-down cells. However, the specific molecular mechanism how GMAT1 regulating glycolytic reprogramming is unclear, and the upstream regulation mechanism of GMAT1 is still concealed. This study will clarify the above-mentioned issue by using chromosome conformation capture, metabolomics analysis and RNA-pulldown technologies in clinical specimens, in vitro and in vivo experiments, explore the biological function of GMAT1 in colorectal cancer, and provide a theoretical basis for investigating the role of genetic variation and epigenetics in disease development.

全基因组关联分析已发现60余个与大肠癌发生相关的遗传多态性位点（SNP），但其潜在作用机制尚未阐明。申请人前期研究发现大肠癌易感位点rs4925386所在区域可能为增强子序列，该遗传变异可以导致其所在序列增强子活性降低。GTEx数据分析进一步发现rs4925386不同基因型与其上游lncRNA GMAT1表达显著相关，提示rs4925386位点突变后可负调控GMAT1表达。此外，预实验结果发现GMAT1在大肠癌组织中显著上调；RNA-seq及GSEA分析显示敲低GMAT1后，糖酵解通路明显下调。然而GMAT1调节糖酵解重编程的具体分子机制尚不明确，其上游调控机制也有待阐明。本研究将在临床标本和体内外实验中，通过染色体构象俘获、代谢组学分析、RNA-pulldown等技术阐明上述内容，探讨GMAT1在大肠癌发生中的生物学功能，同时也为研究遗传变异和表观遗传学在疾病发生中的作用提供理论依据。

大肠癌是消化系统最常见、致死率最高的恶性肿瘤之一，是威胁人类健康的重大问题。研究证实，大肠癌是环境因素和遗传因素共同作用的结果。影响大肠癌发生的遗传因素主要包括基因突变，拷贝数变异和遗传基因单核苷酸多态性（Single Nucleotide Polymorphism，SNP）。全基因组关联分析已发现60余个与大肠癌发生相关的SNP为位点，但其潜在作用机制尚未阐明。长链非编码RNA（lncRNA）在结直肠癌发生中起关键作用，本研究旨在探究风险型SNP诱导的lncRNA在结直肠癌发生中的作用及具体机制。首先，研究人员发现SNP rs6695584为 1q41基因座中的致病SNP位点，且rs6695584的A>G突变可产生BATF蛋白结合基序，改变增强子的活性，随后转录激活lncRNA-SLCC1表达。临床上，研究人员在两个独立的CRC队列中证实了lncSLCC1在CRC组织中上调，并揭示高表达lncRNA-SLCC1与 CRC 患者不良预后相关。机制上，lncRNA-SLCC1与协同转录因子AHR相互作用并转录激活糖代谢关键酶HK2表达，从而驱动糖酵解途径，加速CRC肿瘤生长。综上述，以上研究结果揭示了风险SNP介导的致癌基因lncRNA-SLCC1通过激活糖酵解途径促进结直肠癌。