期刊
GUT
卷 69, 期 7, 页码 1193-1205出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2019-319639
关键词
METTL3; m(6)A; angiogenesis; glycolysis; gastric cancer
资金
- National Natural Science Foundation of China [81773383, 81370078, 31771628, 81903085]
- Science Foundation for Distinguished Young Scholars of Jiangsu Province [BK20170047]
- Fundamental Research Funds for the Central Universities [021414380439]
- China Postdoctoral Science Foundation [2019M651808]
Objective N-6-methyladenosine (m(6)A) 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 m(6)A RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant m(6)A 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 m(6)A modification of HDGF mRNA, and the m(6)A reader IGF2BP3 then directly recognised and bound to the m(6)A 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.
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