Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells.

Ana Manuel Machado, Ceu Figueiredo, Eliette Touati, Valdemar Maximo, Sonia Sousa, Valerie Michel, Fatima Carneiro, Finn Cilius Nielsen, Raquel Seruca, Lene Juel Rasmussen

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Abstract

Purpose: Helicobacter pylori is a major cause of gastric carcinoma.To investigate a possible link between bacterial infection and genetic instability of the host genome, we examined the effect of H. pylori infection on known cellular repair pathways in vitro and in vivo.Moreover, various types of genetic instabilities in the nuclear and mitochondrial DNA (mtDNA) were examined. Experimental Design: We observed the effects of H. pylori infection on a gastric cell line (AGS), on C57BL/6 mice, and on individuals with chronic gastritis. In AGS cells, the effect of
H. pylori infection on base excision repair and mismatch repair (MMR) was analyzed by reverse transcription-PCR,Western blot, and activity assays. In mice, MMR expression was analyzed by reverse transcription-PCR and the CA repeat instabilities were examined by Mutation Detection Enhancement gel lectrophoresis.Mutation spectra in AGS cells and chronic gastritis tissuewere
determined by PCR, single-stranded conformation polymorphism, and sequencing. H. pylori vacA and cagA genotyping was determined by multiplex PCR and reverse hybridization.
Results: Following H. pylori infection, the activity and expression of base excision repair and MMR are down-regulated both in vitro and in vivo. Moreover, H. pylori induces genomic instability in nuclear CA repeats in mice and in mtDNA of AGS cells and chronic gastritis tissue, and this effect inmtDNAis associated with bacterial virulence.
Conclusions: Our results suggest that H. pylori impairs central DNA repair mechanisms, inducing a transientmutator phenotype, rendering gastric epithelial cells vulnerable to the accumulation of genetic instability and thus contributing to gastric carcinogenesis in infected individuals.
Original languageEnglish
JournalClinical Cancer Research
Volume15
Pages (from-to)2995-3002
ISSN1078-0432
DOIs
Publication statusPublished - 2009
Externally publishedYes

Cite this

Machado, A. M., Figueiredo, C., Touati, E., Maximo, V., Sousa, S., Michel, V., Carneiro, F., Nielsen, F. C., Seruca, R., & Rasmussen, L. J. (2009). Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clinical Cancer Research, 15, 2995-3002. https://doi.org/10.1158/1078-0432.CCR-08-2686