Long non-coding RNA NRAV in the 12q24.31 risk locus drives gastric cancer development through glucose metabolism reprogramming
Long non-coding RNA NRAV in the 12q24.31 risk locus drives gastric cancer development through glucose metabolism reprogramming
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DOI：
10.1093/carcin/bgad080
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发表时间：
2023-11-09
期刊：
影响因子：
4.7
通讯作者：
Yan，Caiwang
中科院分区：
文献类型：
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作者：
Zhang，Yan;Gao，Yun;Yan，Caiwang
长链非编码RNA（lncRNA）是介导癌症风险的重要候选者。在这里，我们的目的是确定风险单核苷酸多态性（SNPs）诱导的lncRNA，并探讨其在胃癌（GC）的发展中的作用。通过整合胃癌组织中lncRNA的差异表达分析、正常胃组织和胃癌组织中的表达数量性状位点分析，以及基于胃癌全基因组关联研究和独立验证研究的遗传关联分析，我们发现了4个与胃癌风险相关的lncRNA相关SNPs，包括SNHG 7 [OR = 1.16，95%CI：1.09-1.23]、NRAV（OR = 1.11，95%CI：1.05-1.17）、LINC 01082（OR = 1.16，95%CI：1.08-1.22）和FENDRR（OR = 1.16，95%CI：1.07-1.25）。 我们进一步发现，12q24.31处的功能性SNP rs6489786增加了MEOX 1或MEOX 2在远端增强子处的结合，并导致NRAV的上调。功能检测显示NRAV促进胃癌细胞增殖，抑制胃癌细胞凋亡。从机制上讲，NRAV通过电子传递链降低关键亚基基因的表达，从而驱动葡萄糖代谢从有氧呼吸重编程为糖酵解。这些发现表明，调节lncRNA表达是风险相关变异促进GC发展的关键机制。
Long non-coding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single-nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, includingSNHG7[odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.09–1.23],NRAV(OR = 1.11, 95% CI: 1.05–1.17),LINC01082(OR = 1.16, 95% CI: 1.08–1.22) andFENDRR(OR = 1.16, 95% CI: 1.07–1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in up-regulation ofNRAV. The functional assays revealed thatNRAVaccelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically,NRAVdecreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development.