Zou Jiang, Zhong Xiaowu, Zhou Xi, Xie Qiyue, Zhao Zhao, Guo Xiaolan, Duan Yixiang
Research Center of Analytical Instrumentation, Key Laboratory of Bio-resource and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, 610065, Sichuan, China.
Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
Biochem Biophys Res Commun. 2021 Nov 26;580:48-55. doi: 10.1016/j.bbrc.2021.05.048. Epub 2021 Oct 5.
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal human cancers with a lower 5-year survival rate. N6-methyladenosine (mA) methylation, an important epigenetic modification, has been reported to associate with physiological and pathological processes of cancers. However, its role in ESCC remains unclear. In this work, we found that the mA levels were elevated in ESCC cancer tissues and ESCC cells. The PPI network demonstrated that METTL3, METTL14, WTAP, RBM15, and KIAA1429 were all significantly associated with each other. Moreover, we found a significant upregulation of METTL3 mRNA and protein amounts in ESCC tissues. The METTL3 mRNA expression level of tissues had associations with ESCC differentiation extent and sex (p < 0.05). The METTL3 mRNA expression level of tissues, sensitivity for diagnosing ESCC was 75.00%, specificity was 72.06% and area under the ROC curve was 0.8030. Depletion of METTL3 markedly diminished mA levels in human ESCC cell lines and METTL3 overexpression restored the reduction in mA levels. These results suggested that METTL3 is the primary enzyme that modulates mA methylation and a critical regulatory factor in ESCC. Additionally, METTL3 knockdown significantly suppressed the ESCC cell proliferation, while METTL3 overexpression markedly promoted ESCC cell proliferation both in cell and animal models. These results demonstrated that METTL3 promotes ESCC development. Furthermore, METTL3 may modulate the cell cycle of ESCC cells through a p21-dependent pattern. METTL3-guided mA modification may contribute to the progression of ESCC via the p21-axis. Our study is the first investigation to report that METTL3-mediated mA methylation plays a crucial role in ESCC oncogenesis and highlights that METTL3 might be a potential biomarker and therapeutic target for ESCC patients.
食管鳞状细胞癌（ESCC）是最致命的人类癌症之一，5年生存率较低。N6-甲基腺苷（m⁶A）甲基化是一种重要的表观遗传修饰，据报道与癌症的生理和病理过程相关。然而，其在ESCC中的作用仍不清楚。在这项研究中，我们发现ESCC癌组织和ESCC细胞中的m⁶A水平升高。蛋白质-蛋白质相互作用（PPI）网络表明，METTL3、METTL14、WTAP、RBM15和KIAA1429之间均存在显著关联。此外，我们发现ESCC组织中METTL3 mRNA和蛋白含量显著上调。组织的METTL3 mRNA表达水平与ESCC分化程度和性别相关（p < 0.05）。组织的METTL3 mRNA表达水平对ESCC的诊断敏感性为75.00%，特异性为72.06%，受试者工作特征曲线（ROC）下面积为0.8030。敲低METTL3可显著降低人ESCC细胞系中的m⁶A水平，而过表达METTL3可恢复m⁶A水平的降低。这些结果表明，METTL3是调节m⁶A甲基化的主要酶，也是ESCC中的关键调节因子。此外，在细胞和动物模型中，敲低METTL3可显著抑制ESCC细胞增殖，而过表达METTL3则明显促进ESCC细胞增殖。这些结果表明，METTL3促进ESCC的发展。此外，METTL3可能通过依赖p21的模式调节ESCC细胞的细胞周期。METTL3指导的m⁶A修饰可能通过p21轴促进ESCC的进展。我们的研究是首次报道METTL3介导的m⁶A甲基化在ESCC肿瘤发生中起关键作用，并强调METTL3可能是ESCC患者的潜在生物标志物和治疗靶点。
