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

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

Associate Professorship of Medical Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	358
Journal	Cell Death Discovery
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41420-022-01134-x
State	Published - Dec 2022

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Hinsenkamp, I., Köhler, J. P., Flächsenhaar, C., Hitkova, I., Meessen, S. E., Gaiser, T., Wieland, T., Weiss, C., Röcken, C., Mowat, M., Quante, M., Taxauer, K., Mejias-Luque, R., Gerhard, M., Vogelmann, R., Meindl-Beinker, N., Ebert, M., & Burgermeister, E. (2022). Functional antagonism between CagA and DLC1 in gastric cancer. Cell Death Discovery, 8(1), Article 358. https://doi.org/10.1038/s41420-022-01134-x

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title = "Functional antagonism between CagA and DLC1 in gastric cancer",

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.",

author = "Isabel Hinsenkamp and K{\"o}hler, {Jan P.} and Christoph Fl{\"a}chsenhaar and Ivana Hitkova and Meessen, {Sabine Eberhart} and Timo Gaiser and Thomas Wieland and Christel Weiss and Christoph R{\"o}cken and Michael Mowat and Michael Quante and Karin Taxauer and Raquel Mejias-Luque and Markus Gerhard and Roger Vogelmann and Nadja Meindl-Beinker and Matthias Ebert and Elke Burgermeister",

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year = "2022",

month = dec,

doi = "10.1038/s41420-022-01134-x",

language = "English",

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Hinsenkamp, I, Köhler, JP, Flächsenhaar, C, Hitkova, I, Meessen, SE, Gaiser, T, Wieland, T, Weiss, C, Röcken, C, Mowat, M, Quante, M, Taxauer, K, Mejias-Luque, R, Gerhard, M, Vogelmann, R, Meindl-Beinker, N, Ebert, M & Burgermeister, E 2022, 'Functional antagonism between CagA and DLC1 in gastric cancer', Cell Death Discovery, vol. 8, no. 1, 358. https://doi.org/10.1038/s41420-022-01134-x

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AU - Hinsenkamp, Isabel

AU - Köhler, Jan P.

AU - Flächsenhaar, Christoph

AU - Hitkova, Ivana

AU - Meessen, Sabine Eberhart

AU - Gaiser, Timo

AU - Wieland, Thomas

AU - Weiss, Christel

AU - Röcken, Christoph

AU - Mowat, Michael

AU - Quante, Michael

AU - Taxauer, Karin

AU - Mejias-Luque, Raquel

AU - Gerhard, Markus

AU - Vogelmann, Roger

AU - Meindl-Beinker, Nadja

AU - Ebert, Matthias

AU - Burgermeister, Elke

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41420-022-01134-x

DO - 10.1038/s41420-022-01134-x

M3 - Article

AN - SCOPUS:85135786884

SN - 2058-7716

VL - 8

JO - Cell Death Discovery

JF - Cell Death Discovery

IS - 1

M1 - 358

ER -

Functional antagonism between CagA and DLC1 in gastric cancer

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