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Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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2019 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, no 12, article id e13099Article in journal (Refereed) Published
Abstract [en]

Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 21, no 12, article id e13099
Keywords [en]
APC, bacteria and cancer, bacterial genotoxin, DNA damage response, DNA repair, organotypic del, tumour-suppressor gene
National Category
Microbiology
Identifiers
URN: urn:nbn:se:umu:diva-167179DOI: 10.1111/cmi.13099ISI: 000482652700001PubMedID: 31414579Scopus ID: 2-s2.0-85071087704OAI: oai:DiVA.org:umu-167179DiVA, id: diva2:1384665
Available from: 2020-01-10 Created: 2020-01-10 Last updated: 2023-01-23Bibliographically approved
In thesis
1. Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
Open this publication in new window or tab >>Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Effekter av bakteriella genotoxiner på immunmodulering, kronisk inflammation och cancerutveckling
Abstract [en]

The intestinal microbiome of Inflammatory Bowel Disease and colorectal cancer patients is enriched in genotoxin-producing bacteria, which cause DNA damage in the host cells.

Genotoxins have recently been identified as a novel family of effectors produced by pathogenic and commensal bacteria. At present, only three types of bacterial genotoxins have been identified: colibactin, produced by some Escherichia coli strains; cytolethal distending toxins, produced by several Gram-negative pathogens; and the typhoid toxin, produced by Salmonella enterica serovar Typhi.

Exposure to high toxin doses activates the classical DNA damage response, which consequently blocks proliferation and eventually induces death in mammalian cells. However, exposure to low toxin doses has shown to promote classical signs of carcinogenesis in vitro, such as cell survival and acquisition of genomic instability. Despite an extensive characterization of their mode of action in vitro, we have a poor understanding of genotoxins´ role in chronic infection and, considering the genotoxic potential, of their carcinogenic capacity. To investigate further the role played by the genotoxins, we focused specifically on Salmonella Typhi, since it is the only genotoxin-producing bacterium that induces a chronic infection associated with increased risk of tumor development in humans. 

The results presented in this thesis show that these unusual bacterial effectors are not classical toxins, but rather act as immunomodulators, highlighting a complex and tissue-specific crosstalk between two highly conserved stress responses: the immune response and the DNA damage response. 

Our data indicate that the impact of genotoxin-producing bacteria on the modulation of the host mucosal response is still poorly characterized and suggest that the host-microbe interaction and the tissue microenvironment are the key players in determining the outcome of the infection and the toxin carcinogenic potential. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 93
National Category
Immunology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-203905 (URN)978-91-7855-971-8 (ISBN)978-91-7855-972-5 (ISBN)
Public defence
2023-02-24, Major Groove, Department of Molecular Biology, University hospital area, building 6L., Umeå, 09:00 (English)
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Available from: 2023-02-03 Created: 2023-01-23 Last updated: 2023-01-25Bibliographically approved

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Bergonzini, AnnaFrisan, Teresa

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