Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Cancer Med. 2020 Apr;9(8):2859-2867. doi: 10.1002/cam4.2918. Epub 2020 Feb 18.
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.
METTL3 是一种 RNA 甲基转移酶，参与胚胎发育和癌症中细胞分化和增殖的调控。本研究旨在探讨 METTL3 在肝细胞癌 (HCC) 中的功能和潜在机制。我们评估了 100 例 HCC 病例和 TCGA 数据集的 METTL3 表达和预后意义。在 HCC 病例中，METTL3 的 RNA 和蛋白表达均显著上调，并与预后不良相关。HCC 标本转录谱的基因集富集分析显示，METTL3 表达与葡萄糖代谢受损和 mTOR 信号通路有关。在 Huh-7 和 SMMC-7721 HCC 细胞中，通过 siRNA 干扰下调 METTL3 抑制糖酵解能力，这可以通过减少细胞内葡萄糖摄取和乳酸产生来证明。在机制方面，我们发现 METTL3 的下调会损害 mTORC1 活性，在 Rapamycin 处理的 HCC 细胞中进一步沉默 METTL3 不能降低 mTORC1 的磷酸化水平和糖酵解活性。最后，我们观察到下调 METTL3 与糖酵解抑制剂 2-脱氧葡萄糖 (2-DG) 协同抑制体外肿瘤生长。我们的研究提供了证据表明，METTL3 参与 HCC 中糖酵解活性的调节，提示通过抑制 METTL3 抑制糖酵解可能是治疗 HCC 的一种潜在策略。
