Roles Of NF-κB And STAT3 Pathways In Ulcerative Colitis-associated Carcinogenesis: Based On A AOM-DSS Mouse Model

Background and Objectives:Large scale clinical investigation had revealed that ulcerative colitis (UC) is correlated with colorectal carcinogenesis. Patients with UC have an increased risk of colorectal cancer (CRC), which is also a major cause of death in these patients. It has been well documented there is an "inflammation-dysplasia-carcinoma" sequential pathological processes involved in the ulcerative colitis associated colorectal carcinogenesis. However, the exact mechanism and the major signaling pathways behind these processes have not yet been elucidated. To explore the roles of two major inflammation-related pathways NF-κB and STAT3 and their target genes in these processes, we assayed the expression of p65, p-STAT3, COX-2, Bcl-xL and PCNA in different pathologic stages of a colitis-associated cancer (CAC) mouse model by means of immunohistochemistry.Methods:We used two chemical reagents, azoxymethane (AOM) and dextran sulfate sodium salt (DSS), to establish a CAC mouse model. Mice were sacrificed at indicated time and their large bowels were observed and collected. The expression of p65, p-STAT3, COX-2, Bcl-xL and PCNA in different pathologic stages, ie. normal, inflammation, dysplasia and carcinoma, were assayed by immunohisto-chemistry. ANOVA test and correlation analysis were performed on the expression levels of the five proteins to elucidate the dynamic changing regularity of the key molecules of NF-κB and STAT3 signaling pathways. Results:p65 and Bcl-xL were elevated significantly in the inflammatory, dysplasia and cancerous tissues comparing to normal tissues respectively, and their expression levels elevated progressively in the "inflammation-dysplasia-carcinoma" sequential pathological processes. Expression levels of p-STAT3 were significantly higher in the inflamed and cancerous tissues than normal tissues. Elevated COX-2 and PCNA were detected in the dysplasia and cancerous tissues comparing to normal and inflammatory tissues, especially in carcinoma. The correlation analysis indicated that expression level of p65 had a positive correlation with Bcl-xL and PCNA; p-STAT3 had a positive correlation with Bcl-xL and COX-2; while Bcl-xL had a positive correlation with COX-2 and PCNA.Conclusions:We observed the "inflammation-dysplasia-carcinoma" sequential pathological processes in AOM/DSS induced CAC mouse model. NF-κB and STAT3 signaling pathway was sustained activated (as assayed by its downstream targets such as COX-2,Bcl-xL and PCNA) in this processes and their interactions may contribute to carcinogenesis via promoting cell proliferation and inhibiting apoptosis in the "inflammation-dysplasia-carcinoma" processes of CAC.