Cancer Res. 2014 Sep 12. pii: canres.0870.2014.

Del Reino P, Alsina-Beauchamp D, Escós A, Cerezo-Guisado MI, Risco A, Aparicio N, Zur R, Fernandez-Estevez M, Collantes E, Montans J, Cuenda A.

p38 mitogen-activated protein kinase (MAPK) signalling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumourigenesis, 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 tumourigenesis remains controversial and their function in inflammation-associated cancer has not been studied.

We analysed the role of p38γ and p38δ in colon cancer associated to colitis, using the azoxymethane/dextran sodium sulphate 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 tumour 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 chimaeric mice with transplanted p38γ/δ^-/- bone marrow (BM) had less tumours than WT mice transplanted with WT BM, whereas tumour number was significantly increased in p38γ/δ^-/- chimaeric mice with WT BM compared to p38γ/δ^-/- mice transplanted with p38γ/δ^-/- BM.

Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of haematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.