Functional antagonism between CagA and DLC1 in gastric cancer.
Isabel HinsenkampJan P KöhlerChristoph FlächsenhaarIvana HitkovaSabine Eberhart MeessenTimo GaiserThomas WielandChristel WeißChristoph RoeckenMichael R A MowatMichael QuanteKarin TaxauerRaquel Mejías-LuqueMarkus GerhardRoger VogelmannNadja Meindl-BeinkerMatthias EbertElke BurgermeisterPublished in: Cell death discovery (2022)
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.
Keyphrases
- helicobacter pylori
- induced apoptosis
- helicobacter pylori infection
- cell cycle arrest
- escherichia coli
- newly diagnosed
- stem cells
- magnetic resonance
- squamous cell carcinoma
- high glucose
- ejection fraction
- signaling pathway
- pseudomonas aeruginosa
- cell death
- chronic kidney disease
- endoplasmic reticulum stress
- metabolic syndrome
- cell proliferation
- insulin resistance
- transcription factor
- high resolution
- low grade
- single molecule
- contrast enhanced
- high grade