Trabajo presentado en el 44º Congreso Nacional de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Málaga (España) del 06 al 09 de septiembre de 2022.Chronic inflammation in inflammatory bowel disease (IBD) is a risk factor for Colorectal cancer (CRC) development, but our understanding of this interplay at a molecular level is still limited. p38γ and p38δ, are central in the development of mouse colitis-associated CRC (CAC) by modulating the inflammatory immune response. However, their implication in human CRC and IBD is not well defined. In this study we perform an integrative analysis of p38γ and p38δ mRNA and
protein expression and activation in human patients; using human CRC derived organoids and plasma samples, as well as data from different human CRC and IBD mRNA databases. We found that, p38δ levels were decreased, whereas p38γ expression and phosphorylation were significantly increased in CRC compared to normal colon samples. This increase correlated with the expression of genes implicated in inflammation. Examine of p38γ/p38δ in IBD patients showed that p38γ mRNA and protein levels were increased in Crohn’s disease and ulcerative colitis patients. Contrary, p38δ mRNA was significantly decreased. We also investigated the expression of miRNAs, miR-128-2, miR133a and miR-155, implicated in inflammation and cancer development. In mouse model of colitis and CAC, miR128-2 level was regulated by p38γ/p38δ. In the plasma of IBD and CRC patients, miR128-2 was increased compared to healthy donors, and this correlated with p38γ and p38δ levels. Our results show an opposite regulation of p38γ and p38δ in both CRC and IBD; and suggest that p38γ acts as a link between colitis and CRC by favouring an inflammatory environment that promotes tumour development. We provided evidence that p38γ/p38δ, together with miR-128-2, can be useful as biomarkers, and as potential treatment targets, for colitis and early-stage CRC
