METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells

文献类型： 外文期刊

第一作者： Wang, Jinyong

作者： Wang, Jinyong;Liang, Ruifang;Lin, Yongjian;Wei, Laiyou;Chen, Shanze;Wang, Jinyong;Wang, Jinyong;Ling, Dakai;Peng, Minhua;Wen, Huihong;Shi, Lulin;Li, Huayun;Liu, Tao;Wen, Huihong;Zhang, Guangzhi;Ling, Dakai

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关键词： METTL3; Myeloid-derived suppressive cells; Tumor microenvironment; Inflammatory responses; Ovarian cancer; m6A

期刊名称：CELL AND BIOSCIENCE （ 影响因子：7.5； 五年影响因子：7.9 ）

ISSN：

年卷期： 2023 年 13 卷 1 期

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收录情况： SCI

摘要： BackgroundOvarian cancer (OC) typically develops an immunosuppressive microenvironment by funtional changes of host immune cells. Dysregulated m6A level is associated with cancer progression via the intrinsic oncogenic pathways. However, the role of m6A in regulating host immune cell function during anti-tumor immunity needs comprehensive analysis. This study aimed to investigate the role of METTL3, a catalytic subunit of the methyltransferase complex, in regulating host immune cell response against OC.MethodsIn this study, myeloid-specific Mettl3 gene knockout (Mettl3-cKO) mice were bred using the Cre-LoxP system. Intraperitoneally injection of ID8 cells was used as a syngeneic OC model. Furthermore, the compositions of immune cell populations were analyzed by flow cytometry and single-cell sequencing. Moreover, chemokines and cytokines secretion were assessed using ELISA. Lastly, the role of METTL3 in regulating IL-1 beta secretion and inflammasome activation in bone marrow-derived macrophages cocultured with ID8 cells was specified by ELISA and immunoblotting.ResultsIt was revealed that OC cell growth was enhanced in Mettl3-cKO mice. Furthermore, a shift of decreased M1 to increased M2 macrophage polarization was observed during OC progression. Moreover, Mettl3 depletion in myeloid lineage cells increased secretion of CCL2 and CXCL2 in peritoneal lavage fluild. Interestingly, Mettl3 deficiency enhanced IL-1 beta secretion induced by viable ID8 cells independent of inflammasome activation and cell death. Therefore, OC cells in tumor-bearing mice trigger a slight inflammatory response with a low-to-moderate secretion of pro-inflammatory cytokines and chemokines.ConclusionThis study provides new insights into METTL3-mediated m6A methylation, which regulates host immune response against OC.

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