Pro-Oncogenic Role of Alternative p38 Mitogen-Activated Protein Kinases p38γ and p38δ, Linking Inflammation and Cancer in Colitis-Associated Colon Cancer

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 p38 alpha MAPK (MAPK14) proteins p38 gamma (MAPK12) and p38 delta (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 p38 gamma and p38 delta in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38 gamma-, p38 delta-, and p38 gamma/delta-deficient (p38 gamma/delta(-/-)) mice. We found that p38 gamma/delta deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38 gamma/delta(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38 gamma/delta(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38 gamma/delta(-/-) chimeric mice with WT bone marrow compared with p38 gamma/delta(-/-) mice transplanted with p38 gamma/delta(-/-) bone marrow. Together, our results establish that p38 gamma and p38 delta are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38 gamma and p38 delta as potential targets for cancer therapy. (C) 2014 AACR.