Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China.
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.
Gut. 2020 Jul;69(7):1193-1205. doi: 10.1136/gutjnl-2019-319639. Epub 2019 Oct 3.
N-methyladenosine (mA) 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).
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.
The level of mA RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant mA 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 mA modification of HDGF mRNA, and the mA reader IGF2BP3 then directly recognised and bound to the mA 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.
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.
N6-甲基腺苷（m6A）RNA 甲基化及其相关甲基转移酶 METTL3 通过调节 RNA 功能参与肿瘤的发生和发展。本研究探讨了 METTL3 在胃癌（GC）中的生物学功能和临床意义。
采用组织微阵列和免疫组织化学染色分析评估人类 GC 队列中 METTL3 表达的预后价值。在体外和体内确定 METTL3 在 GC 肿瘤生长和肝转移中的生物学作用和机制。
GC 中 m6A RNA 的水平显著增加，METTL3 是参与丰富 m6A RNA 修饰的主要调节剂。GC 组织中 METTL3 的表达显著升高，并与预后不良相关。多变量 Cox 回归分析显示，METTL3 表达是人类 GC 患者的独立预后因素和有效预测因子。此外，METTL3 过表达促进 GC 细胞在体外和体内的增殖和肝转移。机制上，METTL3 启动子中 P300 介导的 H3K27 乙酰化激活诱导 METTL3 转录，从而刺激 HDGF mRNA 的 m6A 修饰，mA 阅读器 IGF2BP3 随后直接识别并结合到 HDGF mRNA 的 mA 位点，并增强 HDGF mRNA 的稳定性。分泌的 HDGF 促进肿瘤血管生成，而核内 HDGF 激活 GLUT4 和 ENO2 的表达，随后 GC 细胞中的糖酵解增加，这与随后的肿瘤生长和肝转移相关。
METTL3 表达升高促进 GC 中的肿瘤血管生成和糖酵解，表明 METTL3 表达是人类 GC 的潜在预后生物标志物和治疗靶点。
