Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F23%3A00616971" target="_blank" >RIV/68378050:_____/23:00616971 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.science.org/doi/10.1126/sciadv.adh0322" target="_blank" >https://www.science.org/doi/10.1126/sciadv.adh0322</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/sciadv.adh0322" target="_blank" >10.1126/sciadv.adh0322</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells

Popis výsledku v původním jazyce

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori-induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)-positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.

Název v anglickém jazyce

Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells

Popis výsledku anglicky

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori-induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)-positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Science Advances

ISSN

2375-2548

e-ISSN

2375-2548

Svazek periodika

9

Číslo periodika v rámci svazku

46

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

eadh0322

Kód UT WoS článku

001125318400006

EID výsledku v databázi Scopus

2-s2.0-85177103583