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Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway
Open accessAbstract
Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-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 β-catenin signaling in cancer.
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“AvrA, a pathogenic product of Salmonella, has been shown to activate β-catenin signals and enhance colonic tumorigenesis.99”
From The gut microbiota and host health: a new clinical frontier (2016) · cites this paper as [99]
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“In the same direction, the Salmonella enterica effector avirulence protein A (AvrA) is able to translocate into host’s cells and activate β-catenin via its intrinsic de-ubiquitinase activity [70].”
From Gut Microbiota and Cancer: From Pathogenesis to Therapy (2019) · cites this paper as [70]
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Metadata
- Authors
- Lu, R., Wu, S., Zhang, Y.-G., Xia, Y., Liu, X., Zheng, Y., Chen, H., Schaefer, K. L., Zhou, Z., Bissonnette, M., Li, L., & Sun, J.
- Affiliations
- Rush University (US)
- University of Rochester (US)
- University of Rochester Medicine (US)
- University of Chicago (US)
- Stowers Institute for Medical Research (US)
- Corresponding author
- Sun, J
- Venue
- Oncogenesis
- Published
- 2014-06-09
- Volume
- 3
- Issue
- 6
- Pages
- e105-e105
- ISSN
- 2157-9024 (ISSN-L)
- PMC
- PMC4150214
- OpenAlex
- W1968540478
- Cited by
- 206
- References
- 47
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 21 · 2023: 27 · 2022: 16 · 2021: 26 · 2020: 18 · 2019: 9 · 2018: 11 · 2017: 13 · 2016: 10 · 2015: 13 · 2014: 2
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Oncogenesis (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- National Cancer Institute (R01CA164124)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK075386, DK075386, KO1-DK-075386)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Keywords
- avrA, Salmonella typhimurium, colon carcinogenesis, β-catenin signaling, chronic bacterial infection, cancer stem cells, BMI1, matrix metalloproteinase-7, cyclin D1, stem/progenitor cells, gut microbiota
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