title: Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer.
abstract: p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38γ and p38δ in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38γ-, p38δ-, and p38γ/δ-deficient (p38γ/δ(-/-)) mice. We found that p38γ/δ deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38γ/δ(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38γ/δ(-/-) chimeric mice with WT bone marrow compared with p38γ/δ(-/-) mice transplanted with p38γ/δ(-/-) bone marrow. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Del Reino
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Dayanira
authors.initials: D
authors.lastname: Alsina-Beauchamp
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Escós
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Ma Isabel
authors.initials: MI
authors.lastname: Cerezo-Guisado
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Risco
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Aparicio
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Rafal
authors.initials: R
authors.lastname: Zur
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Marian
authors.initials: M
authors.lastname: Fernandez-Estévez
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Collantes
authors.affiliation: Centro Anatomopatológico, Camino de Vinateros, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Montans
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain. acuenda@cnb.csic.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Cuenda
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003092:Colitis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics* / Q000378:metabolism; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics* / Q000378:metabolism
chemical_list: D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13