Abstract LB-281: Enteric bacterial protein AvrA enhances tumorigenesis through activating intestinal STAT/beta-catenin signaling pathways
Authors: Lu Rong , Wu Shaoping , Liu Xingyin , Zhang Yong-guo , Xia Yinglin , Sun Jun 
Published: August 2014

Enteric bacteria play an important role in the pathogenesis of colon cancer. More than 1000 species of bacteria coexist in the human colon. The number of microbial cells is about 10 times larger than the number of eukaryotic cells in the human body. Due to the complexity of the gut flora, identification of the specific microbial agents contributing to colon cancer remains challenging. How bacterial products directly contribute to colorectal cancer is still unknown. Many researchers have taken advantage of the colitis induced by Salmonella Typhimurium to study the early phase of inflammation and infection. A few reports have been on chronic infection in vivo.

Bacteria can modulate the host by secreting bacterial effector proteins to the host cells. AvrA is a pathogenic gene of Salmonella and E.coli, whose encoded protein is inserted into intestinal mucosa. AvrA influences eukaryotic cell pathways utilizing ubiquitin and acetylation. We hypothesize that the bacterial effector AvrA activates the STAT/beta-catenin pathway to promote colonic tumorigenesis.

In the current study, we investigated a chronic bacterial infected cancer model with Salmonella Typhimurium colonization in the mouse intestine for 49 weeks. Mice were colonized with AvrA-sufficient or deficient bacterial strains, then stimulated with a carcinogen azoxymethane (10mg/kg body weight, intraperitoneal injection) and 1% dextran sodium sulfate (induced colitis) in vivo. We found that mice infected with AvrA-expressed bacteria had significantly high incidence of tumor in colon. We found that AvrA expression decreased the phosphorylated-beta-catenin and inhibits the ubiquitination of beta-catenin in mouse colonic epithelial cells in vivo. Additionally, bacterial AvrA expression enhanced the acetylated beta-catenin, which regulates the beta-catenin transcription activity and stabilizes beta-catenin. Moreover, we found the infected colon had higher STAT 1 and 3 expressions. Inflammatory cytokines such as IL-6 and INF-gamma in serum were increased. The STAT pathway was activated by infection and promoted epithelial cancer. STAT and its acute STAT activation promoted inflammation in the infected colon. Overall, AvrA activation of the STAT/beta-catenin pathway promoted colonic tumorigenesis. Our findings provide important insights into how a bacterial effector protein contributes to the development of colon cancer. We believe that determining the responses and underlying mechanisms by which bacteria modulate the STAT/beta-catenin pathway will identify novel approaches to target the specific signal pathway that contributes to tumorigenesis. Our findings can also be applied to the risk assessment and prevention of colon carcinogenesis.

This work was supported by NIH DK075386 and ACS RSG-09–075–01-MBC to Jun Sun.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-281. doi:10.1158/1538-7445.AM2011-LB-281