MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity.

Autor: Sheng YH; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Wong KY; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Seim I; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.; Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Brisbane, QLD, 4012, Australia.; Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Brisbane, QLD, 4102, Australia.; Integrative Biology Laboratory, College of Life Sciences, Nanjing Normal University, 210023, Nanjing, China., Wang R; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., He Y; Cancer Biology Group, Mater Research Institute, University of Queensland, Woolloongabba, Brisbane, QLD, 4101, Australia., Wu A; Bones and Immunology Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Patrick M; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Lourie R; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.; Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Schreiber V; Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Giri R; Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Ng CP; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Popat A; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.; School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia., Hooper J; Cancer Biology Group, Mater Research Institute, University of Queensland, Woolloongabba, Brisbane, QLD, 4101, Australia., Kijanka G; Immune Profiling & Cancer Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Florin TH; Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Begun J; Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia., Radford KJ; Cancer Immunotherapies Group, Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4101, Australia., Hasnain S; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia. sumaira.hasnain@mater.uq.edu.au., McGuckin MA; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia. michael.mcguckin@unimelb.edu.au.; Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia. michael.mcguckin@unimelb.edu.au.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2019 Nov; Vol. 38 (48), pp. 7294-7310. Date of Electronic Publication: 2019 Aug 19.
DOI: 10.1038/s41388-019-0951-y
Abstrakt: Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103 + dendritic cells and CD8 + T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.
Databáze: MEDLINE
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