Abstract 4047: Salmonella protein AvrA activates the STAT3 signaling pathway in colon cancer

Abstract

Abstract Salmonella infection in humans can become chronic which leads to low grade persistent inflammation. These chronic infections increase the risk of several gastrointestinal diseases, including cancer. A recent study has shown that antibody against Salmonella flagellin was higher in colorectal cancer and pre-cancer cases than controls in two distinct populations in US and the Netherlands and that dietary intake is the one of the mediating factors, suggesting a potential link of Salmonella to colorectal cancer. Salmonella AvrA is a multifunctional protein that influences eukaryotic cell pathways by regulating ubiquitination and acetylation. In an animal model, we have demonstrated that infection with AvrA expressing Salmonella induces beta-catenin signals and enhances colonic tumorigenesis. Beta-catenin signaling is a key player in intestinal proliferation and tumorigenesis. The relative contributions of AvrA-induced proliferation and inflammation on tumorigenesis, however, are unknown. STAT3 is activated in chronically inflamed intestines in human inflammatory bowel diseases and in colitis-associated colon cancer. In the current study, mice were colonized with Salmonella AvrA-sufficient or AvrA-deficient bacterial strains. Then, inflammation-associated colon cancer was induced through the use of azoxymethane/dextran sulfate sodium. We determined that AvrA expressing bacteria activated the STAT3 pathway, which is predicted to increase inflammation, enhance proliferation, and promote tumorigenesis. Transcriptional activity of STAT3 and its target genes were up-regulated by Salmonella expressing AvrA, thus promoting proliferation and intestinal tumorigenesis. Our current findings provide new insights regarding a STAT3-dependent mechanism by which the specific bacterial product AvrA enhances the development of infection-associated colon cancer. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for ant-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of STAT/β-catenin signaling in colon cancer. Citation Format: Rong Lu, Shaoping Wu, Yong-Guo Zhang, Yinglin Xia, Zhongren Zhou, Ikuko Tako, Hui Dong, Marc Bissonnette, Jun Sun. Salmonella protein AvrA activates the STAT3 signaling pathway in colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4047.