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

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

doi:10.1186/s13578-023-01149-6

Cell & Bioscience (Nov 2023)

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

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

Affiliations

Jinyong Wang: Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology)
Dakai Ling: Shenzhen International Institute for Biomedical Research
Lulin Shi: Department of Hepatobiliary and Pancreas Surgery, Shenzhen People’s Hospital
Huayun Li: Annoroad Gene Technology Corporation
Minhua Peng: Shenzhen International Institute for Biomedical Research
Huihong Wen: Shenzhen International Institute for Biomedical Research
Tao Liu: Annoroad Gene Technology Corporation
Ruifang Liang: Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology)
Yongjian Lin: Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology)
Laiyou Wei: Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology)
Guangzhi Zhang: Institute of Animal Sciences of Chinese Academy of Agriculture Sciences
Shanze Chen: Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, The Second Clinical Medical College, Shenzhen People’s Hospital, Jinan University, The First Affiliated Hospital of Southern University of Science and Technology)

DOI: https://doi.org/10.1186/s13578-023-01149-6
Journal volume & issue: Vol. 13, no. 1
pp. 1 – 16

Abstract

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Abstract Background Ovarian 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. Methods In 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-1β secretion and inflammasome activation in bone marrow-derived macrophages cocultured with ID8 cells was specified by ELISA and immunoblotting. Results It 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-1β 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. Conclusion This study provides new insights into METTL3-mediated m6A methylation, which regulates host immune response against OC.

Published in Cell & Bioscience

ISSN: 2045-3701 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Technology: Chemical technology: Biotechnology; Science: Biology (General); Science: Chemistry: Organic chemistry: Biochemistry
Website: https://cellandbioscience.biomedcentral.com/

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