Inhibition of Rac family protein impairs colitis and colitis-associated cancer in mice.

The prevalence of inflammatory bowel disease (IBD) has increased worldwide and IBD has been demonstrated to promote the development of colorectal cancer. The Rac family of proteins are involved in key mitogenic pathways. However, to the best of our knowledge, no prior studies have investigated the expression and role of Rac on colitis and colitis-associated cancer (CAC). In the current study, Rac expression in patients with colitis was analyzed according to the expression value from NCBI GEO database (GDS3268). EHT-1864, the specific inhibitor of Rac, was intraperitoneally injected to treat mice with dextran sulfate sodium (DSS)-induced acute and chronic colitis and mice with azoxymethane (AOM)/DSS-induced CAC. Furthermore, immune cell infiltration and the expression of several inflammatory cytokines in colon tissues were analyzed by flow cytometry, immunofluorescence, and ELISAs. We demonstrated the upregulation of the Rac family of proteins in colitis. Inhibition of Rac by EHT-1864 treatment was found to have an efficient inhibitory effect on DSS-induced acute and chronic colitis and AOM/DSS-induced CAC development. We also observed that downregulation of Rac family protein expression markedly prevented macrophage and myeloid-derived suppressor cell (MDSC) infiltration in colon tissues and suppressed pro-inflammatory cytokine expression. Our study established a foundation for understanding the role of Rac in colitis and CAC and to provide a novel strategy and target for colitis and CAC therapy.