Investigation Of The Role And Mechanism Of Sildenafil In Colitis Related Tumorigenesis In Mouse

BackgroundRecently,more and more studies focused on the role of tumor microenvironment in tumor development and progression and revealed that changing of tumor microenvironment played a critical role in this progress in many types of neoplasia,including colorectal cancer.Immunity and inflammation are the first two important parts of tumor microenvironment,but relationship between the two parts is still not very clear;neither is it in colorectal cancer.It is reported that colonic inflammation is tightly related with colorectal cancer.For example,patients with inflammatory bowel disease,including ulcerative colitis and Crohn’s disease,are more easily to develop colorectal cancer than the healthy population.Under inflamed microenvironment,continuous tissue destruction,renewal and persistent oxidative damage can trigger mutagenic processes that serve as cancer-initiating events.Furthermore,the continuous presence of inflammatory cytokines may augment tumor progression through promoting excessive cell proliferation and survival.And accumulation of myeloid-derived suppressor cell(MDSCs)was reported to play an important role in this progress.Phosphodiesterases(PDEs)are an important multi-genic enzyme superfamily,including 11 PDE members with different tissue localization,and participate in several cell functions.The enzyme PDE-5 is known to be abundant in various tissues where it hydrolyses cyclic guanosine monophosphate(cGMP),a second messenger of nitric oxide(NO).Solid evidences have demonstrated the prevention role of PDE-5 inhibition in trinitrobenzenesulfonic acid-induced colitis,acetic acid-induced colitis and ischemic colitis in rat.However,the distribution and expression of PDE-5 in colitis-related colorectal cancer is still unclear,not even the function and mechanism.AimsTo construct mouse models of colitis,colorectal cancer and colitis related cancer,investigate the role of PDE-5 in these models,elucidate the mechanism of this role and offer a new way for prevention and treatment of inflammation related colorectal cancer.MethodsWestern blotting and ELISA were performed to detect colonic PDE-5 expression in different models.Sildenafil,a specific PDE-5 inhibitor,was used to treat AOM/DSS-induced and AOM-induced colonic tumorigenesis model and DSS-induced colitis model.The leukocyte infiltration in colonic tissue was examined by flow cytometry.Further matrigel-based invasion assay was employed to determine the effects of Sildenafil on MDSCs in vitro.ResultsWe demonstrated the upregulation of colonic PDE-5 expression and the prevention role of PDE-5 inhibition in AOM/DSS-induced tumorigenesis model.More importantly,PDE-5 inhibitor Sildenafil inhibited colonic tumorigenesis dependent on inflammation and suppressed DSS-induced colitis.Molecular mechanism investigation indicated that Sildenafil inhibited migration of MDSCs but it couldn’t directly inhibit migration of macrophages.ConclusionSildenafil suppresses colorectal tumorigenesis dependent on inflammation.It suppresses colitis and colonic inflammation related tumorigenesis via blocking the recruitment of MDSCs in mouse.