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.
Highlights
Cancer and chronic inflammation are intimately associated [1], for example, in inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn disease, which confer an increased risk for colorectal cancer, one of the most common fatal malignancies worldwide [2]
As we found no major impact of p38g/d deletion on chronic inflammation, we analyzed whether this deletion affected acute colon inflammation in p38g/dÀ/À mice and was, a potential mechanism contributing to decreased tumorigenesis
Tumors from all chimeric mice were histologically similar (Fig. 6D). These data show that p38g/d expression in hematopoietic cells is critical for production of inflammatory mediators and cell recruitment that lead to colon tumor development, and indicate that absence of p38g and p38d in the hematopoietic compartment is responsible for decreased tumorigenesis in p38g/dÀ/À mice
Summary
Cancer and chronic inflammation are intimately associated [1], for example, in inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn disease, which confer an increased risk for colorectal cancer, one of the most common fatal malignancies worldwide [2]. Immune cells, which often infiltrate tumors and preneoplastic lesions, produce a variety of cytokines and chemokines that propagate a localized inflammatory response; they enhance premalignant cell growth and survival by activating signaling pathways such as NF-kB or MAPKs [3, 5] Within this group, the p38MAPKs are central to inflammatory processes and to the production of proinflammatory molecules that contribute to CAC pathogenesis [6]. Studies in immortalized mouse embryonic fibroblasts and in K-Ras–transformed cells lacking p38g or p38d indicated that these kinases can inhibit tumor development by regulating processes associated with malignant cell transformation such as proliferation, contact inhibition and/or migration [25] These findings suggest that p38g and p38d are implicated in linking tumor promotion and/or progression and inflammation. Our study shows the important prooncogenic role of p38g and p38d in a yet unidentified signaling pathway for development of colitis-associated colon tumors, and confirms p38g and p38d as potential targets for colon cancer treatment
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