m6A methyltransferase METTL3 promotes non-small-cell lung carcinoma progression by inhibiting the RIG-I-MAVS innate immune pathway

作者：Tinghui Huang, Xudong Ao, Jie Liu, Chuancheng Sun, Yunfei Dong, Xuechen Yin, Yan Zhang, Xinping Wang, Wenying Li, Jiujiu Cao, Feiyan Pan, Zhigang Hu, Zhigang Guo, Lingfeng He · 发表于：Translational Oncology · 年份：2024 · DOI：10.1016/j.tranon.2024.102230 · 被引用次数：10 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Cancer-related gene regulation

• High METTL3 expression in non-small cell lung cancer cells correlates with increased tumor proliferation. • METTL3 regulates RIG-I-MAVS signaling pathway via m6A modifications, highlighting its critical role in tumor biology. • Mettl3-mediated methylation of DDX58, with YTHDF2 as its methylation reader protein. • Non-small cell lung cancer cells suppress RIG-I-MAVS signaling and immune responses through METTL3-mediated methylation. Our experimental study showed that METTL3 was highly expressed in NSCLC cells and promoted the growth of tumor cells. METTL3 takes N6-methyladenosine (m6A) as the main means of mRNA modification to control the expression and function of RIG-I-MAVS signalling pathway. RIG-I-MAVS constitute the first line frontier in the innate immune defense of human cells. Activation of RIG-I-MAVS signaling can inhibit tumor cell growth and activate the immune microenvironment. Our experimental data reveal that lung cancer cells utilize METTL3-mediated methylation modifications to inhibit the activation of RIG-I-MAVS signaling pathway and immune responses. Our work provides new ideas for biotherapy and immunotherapy. A schematic representation of the molecular mechanism (By Figdraw.) This schematic illustrates that the upregulation of METTL3 suppresses the expression of RIG-I and the activation of its downstream signaling pathways in an m6A-dependent manner. This ultimately leads to reduced secretion of interferon α/β and weakened cytotoxicity of T cells, thereby...