METTL3 is an RNA methyltransferase implicated in the control of cell differentiation and proliferation in embryonic development and cancer. The current study was aimed to explore the function and underlying mechanism of METTL3 in hepatocellular carcinoma (HCC). We evaluated the expression and prognostic significance of METTL3 in 100 HCC cases and TCGA dataset. In HCC cases, both the RNA and protein expression of METTL3 were significantly upregulated and associated with poor prognosis. Gene set enrichment analysis of transcriptional profiles in HCC specimens revealed that METTL3 expression was associated with impaired glucose metabolism and mTOR signal pathway. In Huh-7 and SMMC-7721 HCC cells, downregulation of METTL3 by siRNA interference inhibited glycolytic capacity, which was proved by the decreased intracellular glucose uptake and lactate production. In terms of mechanism, we found mTORC1 activity was impaired by downregulation of METTL3, additional silencing of METTL3 cannot further decrease the phosphorylation level of mTORC1 and glycolysis activity in Rapamycin-treated HCC cells. At last, we observed that downregulation of METTL3 synergizes with the glycolysis inhibitor 2-deoxyglucose (2-DG) to inhibit tumor growth in vitro. Our study provided evidence that METTL3 is involved in the regulation of glycolysis activity in HCC, suggesting that suppression of glycolysis via METTL3 inhibition was a potential treating strategy against HCC.

中文翻译：

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METTL3表达与肝细胞癌中的糖酵解代谢和糖酵解应激敏感性相关。

METTL3是一种RNA甲基转移酶，涉及胚胎发育和癌症中细胞分化和增殖的控制。目前的研究旨在探讨METTL3在肝细胞癌（HCC）中的功能及其潜在机制。我们评估了METTL3在100例HCC病例和TCGA数据集中的表达和预后意义。在HCC病例中，METTL3的RNA和蛋白表达均显着上调并与不良预后相关。HCC标本中转录谱的基因集富集分析表明，METTL3表达与葡萄糖代谢和mTOR信号通路受损有关。在Huh-7和SMMC-7721 HCC细胞中，siRNA干扰下的METTL3下调抑制了糖酵解能力，细胞内葡萄糖摄取和乳酸产生的减少证明了这一点。从机理上讲，我们发现METOR3的下调削弱了mTORC1的活性，METTL3的额外沉默不能进一步降低雷帕霉素处理的HCC细胞中mTORC1的磷酸化水平和糖酵解活性。最后，我们观察到METTL3的下调与糖酵解抑制剂2-脱氧葡萄糖（2-DG）协同作用，从而在体外抑制肿瘤的生长。我们的研究提供了证据，证明METTL3参与了HCC糖酵解活性的调节，这表明通过METTL3抑制抑制糖酵解是一种针对HCC的潜在治疗策略。METTL3的额外沉默不能进一步降低雷帕霉素处理的HCC细胞中mTORC1的磷酸化水平和糖酵解活性。最后，我们观察到METTL3的下调与糖酵解抑制剂2-脱氧葡萄糖（2-DG）协同作用，从而在体外抑制肿瘤的生长。我们的研究提供了证据，证明METTL3参与了HCC糖酵解活性的调节，这表明通过METTL3抑制抑制糖酵解是一种针对HCC的潜在治疗策略。METTL3的额外沉默不能进一步降低雷帕霉素处理的HCC细胞中mTORC1的磷酸化水平和糖酵解活性。最后，我们观察到METTL3的下调与糖酵解抑制剂2-脱氧葡萄糖（2-DG）协同作用，从而在体外抑制肿瘤的生长。我们的研究提供了证据，证明METTL3参与了HCC糖酵解活性的调节，这表明通过METTL3抑制抑制糖酵解是一种针对HCC的潜在治疗策略。