Implicación de p38[gamma] y p38[delta] MAPKs en el desarrollo del cáncer de colon asociado a colitis

Resumen

Colon cancer associated with colitis (CAC) is a subtype of colorectal cancer in which inflammatory and tumorigenic processes converge and is associated with inflammatory bowel disease, such as occurring in ulcerative colitis (UC). To elucidate the factors involved in tumor onset and development, we must analyze immunological and genetic factors. The p38MAPK (mitogen-activated protein kinases) signaling pathway links extracellular signaling to mechanisms that control fundamental cell processes such as growth, proliferation, differentiation, migration, and apoptosis. The p38MAPK family is formed by four members, p38¿, p38ß, p38¿ and p38¿. p38¿ regulates inflammation and malignant transformation, but little is known about the functions of the other p38MAPK isoforms in these processes. The main objective of this thesis was to define the implication of p38¿ and p38¿ in murine models of CAC and UC. For this purpose, we studied the phenotype of wt, p38¿-/-, p38¿-/- and p38¿/¿-/- mice treated with AOM/DSS (Azoxymethane/Dextran sodium sulfate, for the CAC model), for the CAC model) or DSS (for the UC model). Histopathological examination of colon sections from AOM/DSS-treated mice showed larger, more numerous tumors in p38¿-/- and p38¿/¿-/- than in wt and p38¿-/- mice. Analysis of intestinal mucosa showed increased epithelial cell proliferation in p38¿-/- and p38¿/¿-/- compared to wt mice, as well as lower numbers of apoptotic cells in p38¿-/- than in p38¿-/- and p38¿/¿-/- mice. Increase in MMP9 levels, which are generally implicated in CAC, were higher in treated p38¿-/- and p38¿/¿-/- mice than in the other genotypes. These results indicated that p38¿ is implicated in tumor development, regulating processes such as proliferation and apoptosis, and altering levels of protumor proteins such as MMP9. We studied tissue damage and inflammation in hematoxylin/eosin-stained histological sections from the four mouse genotypes after DSS treatment. p38¿-/- mice had the highest degree of inflammation compared with the other genotypes. Analysis of intestinal mucosa showed increased epithelial cell apoptosis in p38¿-/- and p38¿/¿-/- compared to wt mice. Immunofluorescence studies of histological sections showed higher levels of macrophage infiltration in treated p38¿-/- and p38¿/¿-/- than in the other genotypes and less neutrophils infiltration in treated p38¿-/- and p38¿/¿-/- mice in both models (CAC and UC). COX2 protein and mRNA levels, which are linked to inflammatory processes, were higher in treated p38¿-/- mice than in the other genotypes in CAC model. In DSS-treated p38¿-/- mice, pro-inflammatory cytokine levels (IL1ß, IL6 and TNF¿) were higher than in treated wt mice. These findings implicate p38¿ in inflammatory processes such as apoptosis, pro-inflammatory cytokine production and in regulating inflammatory molecules like COX2. The results indicate that although both p38MAPK isoforms are involved in the alterations found in CAC and UC models, the main isoform involved in tumor development is p38¿, whereas p38¿ is involved in inflammatory processes.