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Functional antagonism between CagA and DLC1 in gastric cancer

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 enterochromaffi...

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Main Authors: Hinsenkamp, Isabel (Author) , Köhler, Jan Philipp (Author) , Flächsenhaar, Christoph (Author) , Hitkova, Ivana (Author) , Meessen, Sabine Eberhart (Author) , Gaiser, Timo (Author) , Wieland, Thomas (Author) , Weiß, Christel (Author) , Röcken, Christoph (Author) , Mowat, Michael (Author) , Quante, Michael (Author) , Taxauer, Karin (Author) , Mejías-Luque, Raquel (Author) , Gerhard, Markus (Author) , Vogelmann, Roger (Author) , Meindl-Beinker, Nadja M. (Author) , Ebert, Matthias (Author) , Burgermeister, Elke (Author)
Format: Article (Journal)
Language:English
Published: 13 August 2022
In: Cell death discovery
Year: 2022, Volume: 8, Pages: 1-12
ISSN:2058-7716
DOI:10.1038/s41420-022-01134-x
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41420-022-01134-x
Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41420-022-01134-x
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Author Notes: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 and Elke Burgermeister
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Summary: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.
Item Description:Gesehen am 23.10.2023
Physical Description:Online Resource
ISSN:2058-7716
DOI:10.1038/s41420-022-01134-x

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