title: Salmonella Protein AvrA Activates the STAT3 Signaling Pathway in Colon Cancer.
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. 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 enhance proliferation and promote tumorigenesis. Transcriptional activity of STAT3 and its target genes were upregulated by Salmonella expressing AvrA, thus promoting proliferation and intestinal tumorigenesis. Our findings provide new insights regarding a STAT3-dependent mechanism by which the specific bacterial product AvrA enhances the development of infection-associated colon cancer. These insights might suggest future biomarkers to risk assessment and early detection of infection-related cancer.
authors.affiliation: Department of Biochemistry, Rush University, 1735 W Harrison St, Chicago, IL 60612. USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Biochemistry, Rush University, 1735 W Harrison St, Chicago, IL 60612. USA.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Rush University, 1735 W Harrison St, Chicago, IL 60612. USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Yong-Guo
authors.initials: YG
authors.lastname: Zhang
authors.affiliation: Biostatistics and Computational Biology, University of Rochester.
authors.forename: Yinglin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Pathology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Oncology and Pathology, Wayne State University School of Medicine, Detroit, MI 48201,USA.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology, Xingqiao Hospital, The Third Military Medical University, Chongqing 400037, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Medicine, The University of Chicago, Center for Advanced Medicine, 5758 S Maryland Ave, Chicago, IL 60637, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Bissonnette
authors.affiliation: Department of Biochemistry, Rush University, 1735 W Harrison St, Chicago, IL 60612. USA; Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. Electronic address: junsun7@uic.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002908:Chronic Disease; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012475:Salmonella / Q000502:physiology*; D012480:Salmonella Infections / Q000150:complications* / Q000382:microbiology; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; D016207:Cytokines; D050796:STAT3 Transcription Factor