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Original research
METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance
  1. Qiang Wang1,
  2. Chen Chen2,
  3. Qingqing Ding3,
  4. Yan Zhao4,
  5. Zhangding Wang4,
  6. Junjie Chen2,
  7. Zerun Jiang2,
  8. Yan Zhang1,
  9. Guifang Xu4,
  10. Jingjing Zhang5,
  11. Jianwei Zhou2,
  12. Beicheng Sun1,
  13. Xiaoping Zou4,
  14. Shouyu Wang1,2,6,7
  1. 1 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
  2. 2 Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
  3. 3 Department of Geriatric Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China
  4. 4 Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China
  5. 5 Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province, People’s Republic of China
  6. 6 Center for Public Health Research, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China
  7. 7 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, People’s Republic of China
  1. Correspondence to Professor Shouyu Wang, Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; sywang{at}nju.edu.cn; Professor Beicheng Sun, Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; sunbc{at}njmu.edu.cn; Professor Xiaoping Zou, Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; 13770771661{at}163.com

Abstract

Objective N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation and progression via the regulation of RNA function. This study explored the biological function and clinical significance of METTL3 in gastric cancer (GC).

Design The prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human GC cohort. The biological role and mechanism of METTL3 in GC tumour growth and liver metastasis were determined in vitro and in vivo.

Results The level of m6A RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant m6A RNA modification. METTL3 expression was significantly elevated in GC tissues and associated with poor prognosis. Multivariate Cox regression analysis revealed that METTL3 expression was an independent prognostic factor and effective predictor in human patients with GC. Moreover, METTL3 overexpression promoted GC proliferation and liver metastasis in vitro and in vivo. Mechanistically, P300-mediated H3K27 acetylation activation in the promoter of METTL3 induced METTL3 transcription, which stimulated m6A modification of HDGF mRNA, and the m6A reader IGF2BP3 then directly recognised and bound to the m6A site on HDGF mRNA and enhanced HDGF mRNA stability. Secreted HDGF promoted tumour angiogenesis, while nuclear HDGF activated GLUT4 and ENO2 expression, followed by an increase in glycolysis in GC cells, which was correlated with subsequent tumour growth and liver metastasis.

Conclusions Elevated METTL3 expression promotes tumour angiogenesis and glycolysis in GC, indicating that METTL3 expression is a potential prognostic biomarker and therapeutic target for human GC.

  • METTL3
  • m6A
  • angiogenesis
  • glycolysis
  • gastric cancer

https://doi.org/10.1136/gutjnl-2019-319639

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    Footnotes

    • QW, CC and QD are joint first authors.

    • QW, CC and QD contributed equally.

    • Contributors QW, CC, QD, YZ, ZW, JC, ZJ and YZhao performed the experiments; QW and CC analysed data; GX, JZ, QD, BS and XZ provided the samples; QW and SW wrote the paper; BS and JZhang commented on the study and revised the paper; SW designed the research.

    • Funding This work was supported in part by the National Natural Science Foundation of China (81773383, 81370078, 31771628, 81903085); and the Science Foundation for Distinguished Young Scholars of Jiangsu Province (BK20170047); and the Fundamental Research Funds for the Central Universities (021414380439); and the Project funded by China Postdoctoral Science Foundation (2019M651808).

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The use of human gastric cancer tissues and the waiver of patient consent in this study were approved by the Clinical Research Review Board of the Institutional of the Nantong Cancer Hospital and Nanjing Drum Tower Hospital, respectively. The study was conducted according to the principles expressed in the Declaration of Helsinki.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request.