Long non-coding RNA NRAV in the 12q24.31 risk locus drives gastric cancer development through glucose metabolism reprogramming

Author:

Zhang Yan12,Gao Yun1,Li Fengyuan13,Qi Qi1,Li Qian1,Gu Yuanliang1,Zheng Zhonghua1,Hu Beiping1,Wang Tianpei14,Zhang Erbao12,Xu Hao3,Liu Li5,Tian Tian6,Jin Guangfu1247,Yan Caiwang189ORCID

Affiliation:

1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University , Nanjing , China

2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University , Nanjing , China

3. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing , China

4. Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou , China

5. Institute of Digestive Endoscopy, The First Affiliated Hospital of Nanjing Medical University , Nanjing , China

6. Department of Epidemiology, School of Public Health, Nantong University , Nantong , China

7. Research Center for Clinical Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University , Nanjing , China

8. Department of Immunology, Key Laboratory of Immunological Environment and Disease, Nanjing Medical University , Nanjing , China

9. The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital , Wuxi Medical Center, Wuxi , China

Abstract

Abstract 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, including SNHG7 [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) and FENDRR (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 of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases 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.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Jiangsu Province

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

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