METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance
METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance
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METTL3介导的HDGF mRNA的m(6)A修饰促进胃癌进展并具有预后意义。
DOI：
10.1136/gutjnl-2019-319639
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发表时间：
2020-07-01
期刊：
影响因子：
24.5
通讯作者：
Wang, Shouyu
中科院分区：
文献类型：
--
作者：
Wang, Qiang;Chen, Chen;Wang, Shouyu
目的N-6-甲基腺苷（m（6）A）RNA甲基化及其相关的甲基转移酶L3通过调节RNA功能参与肿瘤的发生和发展。本研究探讨了胃L3在胃癌（GC）中的生物学功能和临床意义。设计胃L3表达的预后价值在人类GC队列中使用组织芯片和免疫组化染色分析进行了评估。结果胃癌组织中m（6）A RNA水平明显升高，胃L3是参与m（6）A RNA修饰的主要调控因子。胃癌组织中L3表达显著升高，与预后不良相关。多因素考克斯回归分析显示，胃L3表达是胃癌患者的独立预后因素和有效预测因子。此外，在体外和体内，胃L3过表达促进GC增殖和肝转移。在机制上，P300介导的H3 K27乙酰化激活在胃L3启动子中诱导胃L3转录，其刺激HDGF mRNA的m（6）A修饰，并且m（6）A阅读器IGF 2BP 3然后直接识别并结合到HDGF mRNA上的m（6）A位点，并增强HDGF mRNA的稳定性。分泌型HDGF促进肿瘤血管生成，而核HDGF激活GLUT 4和ENO 2的表达，随后增加糖酵解在GC细胞，这是与随后的肿瘤生长和肝transferation.Conclusions胃L3的表达升高促进肿瘤血管生成和糖酵解在GC，表明胃L3的表达是一个潜在的预后生物标志物和治疗靶点，为人类GC。
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.