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Inflammation suppresses DLG2 expression decreasing inflammasome formation
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translational Medicine TRIM)ORCID iD: 0000-0002-0471-6896
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. (Infection Biology)
Division of Gastroenterology/Hepatology, Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden.
Department of Surgery, The Sahlgrenska Academy at University of Gothenburg, SU/Östra, Gothenburg, Sweden.
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2022 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 149, no 9, p. 2295-2311Article in journal (Refereed) Published
Abstract [en]

Purpose

Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction.

Methods

The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release.

Results

The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling.

Conclusion

DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes.

Trial registration

NCT03072641.

Place, publisher, year, edition, pages
Springer Nature Switzerland AG , 2022. Vol. 149, no 9, p. 2295-2311
Keywords [en]
DLG2, Inflammasome, NFKBIZ, Ulcerative colitis, Colon cancer
National Category
Gastroenterology and Hepatology Immunology in the medical area
Research subject
Translational Medicine TRIM; Infection Biology
Identifiers
URN: urn:nbn:se:his:diva-21117DOI: 10.1007/s00432-022-04029-7ISI: 000789726400001PubMedID: 35499706Scopus ID: 2-s2.0-85129231846OAI: oai:DiVA.org:his-21117DiVA, id: diva2:1656154
Funder
Royal Physiographic Society in Lund
Note

CC BY 4.0

Simon Keane simon.keane@his.se

Published: 02 May 2022

© 2022 Springer Nature Switzerland AG. Part of Springer Nature.

Springer

We thank the Jane and Dan Olsson foundation, Assar Gabrielssons Foundation, Royal Physiographic Society of Lund and University of Skövde for financial support. We thank the staff at the Centre for Cellular Imaging at the University of Gothenburg for their advice and assistance in fluorescence imaging. A-L. Helminen and H. Björkqvist are acknowledged for help with implementation of the NCT03072641 study and collection of patient samples. We thank L. Munro for clinical database assistance, and J. Flach and M. Åkerström for technical assistance.

Open access funding provided by University of Skövde. Jane and Dan Olsson foundation (2020–2029), Assar Gabrielssons Foundation (FB21-06), Royal Physiographic Society of Lund (NA) and University of Skövde.

The datasets generated during and/or analysed during the current study are available in the R2: genomics analysis visualization platform, http://r2.amc.n listed in the methods by GSE identification number.

Available from: 2022-05-04 Created: 2022-05-04 Last updated: 2022-08-15Bibliographically approved

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Keane, SimonHerring, MatthewEjeskär, Katarina

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