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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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Detalles Bibliográficos
Autores principales: Hinsenkamp, Isabel, Köhler, Jan P., Flächsenhaar, Christoph, Hitkova, Ivana, Meessen, Sabine Eberhart, Gaiser, Timo, Wieland, Thomas, Weiss, Christel, Röcken, Christoph, Mowat, Michael, Quante, Michael, Taxauer, Karin, Mejias-Luque, Raquel, Gerhard, Markus, Vogelmann, Roger, Meindl-Beinker, Nadja, Ebert, Matthias, Burgermeister, Elke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9376073/
https://www.ncbi.nlm.nih.gov/pubmed/35963849
http://dx.doi.org/10.1038/s41420-022-01134-x
Descripción
Sumario: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.