Functional antagonism between CagA and DLC1 in gastric cancer

Isabel Hinsenkamp; Jan P. Köhler; Christoph Flächsenhaar; Ivana Hitkova; Sabine Eberhart Meessen; Timo Gaiser; Thomas Wieland; Christel Weiss; Christoph Röcken; Michael Mowat; Michael Quante; Karin Taxauer; Raquel Mejias-Luque; Markus Gerhard; Roger Vogelmann; Nadja Meindl-Beinker; Matthias Ebert; Elke Burgermeister

doi:10.1038/s41420-022-01134-x

Cell Death Discovery (Aug 2022)

Functional antagonism between CagA and DLC1 in gastric cancer

Isabel Hinsenkamp,
Jan P. Köhler,
Christoph Flächsenhaar,
Ivana Hitkova,
Sabine Eberhart Meessen,
Timo Gaiser,
Thomas Wieland,
Christel Weiss,
Christoph Röcken,
Michael Mowat,
Michael Quante,
Karin Taxauer,
Raquel Mejias-Luque,
Markus Gerhard,
Roger Vogelmann,
Nadja Meindl-Beinker,
Matthias Ebert,
Elke Burgermeister

Affiliations

Isabel Hinsenkamp: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Jan P. Köhler: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Christoph Flächsenhaar: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Ivana Hitkova: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Sabine Eberhart Meessen: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Timo Gaiser: Institute of Pathology, Medical Faculty Mannheim, Heidelberg University
Thomas Wieland: Experimental Pharmacology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University
Christel Weiss: Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University
Christoph Röcken: Institute of Pathology, Christian Albrechts University Kiel
Michael Mowat: CancerCare Manitoba Research Institute, Department of Biochemistry & Medical Genetics, University of Manitoba
Michael Quante: Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, University Medical Center Freiburg
Karin Taxauer: Institute for Med. Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM)
Raquel Mejias-Luque: Institute for Med. Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM)
Markus Gerhard: Institute for Med. Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM)
Roger Vogelmann: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Nadja Meindl-Beinker: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Matthias Ebert: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University
Elke Burgermeister: Department of Medicine II, Medical Faculty Mannheim, Heidelberg University

DOI: https://doi.org/10.1038/s41420-022-01134-x
Journal volume & issue: Vol. 8, no. 1
pp. 1 – 12

Abstract

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Abstract Helicobacter (H.) pylori-induced gastritis is a risk factor for gastric cancer (GC). Deleted-in-liver-cancer-1 (DLC1/ARHGAP7) inhibits RHOA, a downstream mediator of virulence factor cytotoxin-A (CagA) signalling and driver of consensus-molecular-subtype-2 diffuse GC. DLC1 located to enterochromaffin-like and MIST1+ stem/chief cells in the stomach. DLC1+ cells were reduced in H. pylori gastritis and GC, and in mice infected with H. pylori. DLC1 positivity inversely correlated with tumour progression in patients. GC cells retained an N-terminal truncation variant DLC1v4 in contrast to full-length DLC1v1 in non-neoplastic tissues. H. pylori and CagA downregulated DLC1v1/4 promoter activities. DLC1v1/4 inhibited cell migration and counteracted CagA-driven stress phenotypes enforcing focal adhesion. CagA and DLC1 interacted via their N- and C-terminal domains, proposing that DLC1 protects against H. pylori by neutralising CagA. H. pylori-induced DLC1 loss is an early molecular event, which makes it a potential marker or target for subtype-aware cancer prevention or therapy.

Published in Cell Death Discovery

ISSN: 2058-7716 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Science: Biology (General): Cytology
Website: http://www.nature.com/cddiscovery/

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