title: Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC.
abstract: Phosphodiesterase 5 (PDE-5) is a major isoform of cGMP phosphodiesterase in diverse tissues and plays a critical role in regulating intracellular cGMP concentrations. However, the distribution and expression of PDE-5 in colitis-related colon cancer was still unclear, not even the function and mechanism. Western blotting and ELISA were performed to detect colonic PDE-5 expression in AOM/DSS-induced tumorigenesis model. 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 and immunofluorescence staining. Further matrigel-based invasion assay was employed to determine the effects of Sildenafil on myeloid-derived suppressor cell (MDSC)in vitro. We first 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 regulated inflammation microenvironment via directly inhibiting MDSC infiltration in colonic tissue. The study provides solid evidence for the use of PDE-5 inhibitor in preventing and treating colonic inflammation-related tumorigenesis.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical UniversityGuangzhou 510515, Guangdong Province, China; Department of Endoscopy, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer MedicineGuangzhou 510060, Guangdong Province, China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Lin
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Endoscopy, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou 510060, Guangdong Province, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology; Inst. of Gastroenterology of Guangdong Province; Department of Gastroenterology, Nanfang Hospital, Southern Medical University Guangzhou 510515, Guangdong Province, China.
authors.forename: Fachao
authors.initials: F
authors.lastname: Zhi
keywords: Colon cancer; MDSC; PDE-5; Sildenafil; colitis