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

Functional antagonism between CagA and DLC1 in gastric cancer

Cell Death Discov. 2022 Aug 13;8(1):358. doi: 10.1038/s41420-022-01134-x.

Authors

Isabel Hinsenkamp^#¹, Jan P Köhler^#¹, Christoph Flächsenhaar^{1

2}, Ivana Hitkova¹, Sabine Eberhart Meessen¹, Timo Gaiser², Thomas Wieland³, Christel Weiss⁴, Christoph Röcken⁵, Michael Mowat⁶, Michael Quante⁷, Karin Taxauer⁸, Raquel Mejias-Luque⁸, Markus Gerhard⁸, Roger Vogelmann¹, Nadja Meindl-Beinker¹, Matthias Ebert^{1

9

10

11

12}, Elke Burgermeister¹³

Affiliations

¹ Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³ Experimental Pharmacology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴ Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁵ Institute of Pathology, Christian Albrechts University Kiel, Kiel, Germany.
⁶ CancerCare Manitoba Research Institute, Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
⁷ Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, University Medical Center Freiburg, Freiburg, Germany.
⁸ Institute for Med. Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
⁹ DKFZ-Hector Institute at the University Medical Center, Mannheim, Germany.
¹⁰ Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹¹ Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹² Mannheim Cancer Center (MCC), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹³ Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. elke.burgermeister@medma.uni-heidelberg.de.

^# Contributed equally.

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.

Abstract

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