Aberrant DNA Polymerase Beta Enhances H. pylori Infection Induced Genomic Instability and Gastric Carcinogenesis in Mice.

Shengyuan Zhao,Dawit Kidane,Megha Thakur,Alex W. Klattenhoff

doi:10.3390/cancers11060843

Shengyuan Zhao, Dawit Kidane + Show 2 more

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https://doi.org/10.3390/cancers11060843

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Journal: Cancers	Publication Date: Jun 18, 2019
Citations: 5	License type: CC BY 4.0

Affiliation: The University of Texas at Austin

Abstract

H. pylori is a significant risk factor of gastric cancer that induces chronic inflammation and oxidative DNA damage to promote gastric carcinoma. Base excision repair (BER) is required to maintain the genome integrity and prevent oxidative DNA damage. Mutation in DNA polymerase beta (Pol β) impacts BER efficiency and has been reported in approximately 30–40% of gastric carcinoma tumors. In this study, we examined whether reduced BER capacity associated with mutation in the POLB gene, along with increased DNA damage generated by H. pylori infection, accelerates gastric cancer development. By infecting a Pol β mutant mouse model that lacks dRP lyase with H. pylori, we show that reactive oxygen and nitrogen species (RONS) mediated DNA damage is accumulated in Pol β mutant mice (L22P). In addition, H. pylori infection in Leu22Pro (L22P) mice significantly increases inducible nitric oxide synthesis (iNOS) mediated chronic inflammation. Our data show that L22P mice exhibited accelerated H. pylori induced carcinogenesis and increased tumor incidence. This work shows that Pol β mediated DNA repair under chronic inflammation conditions is an important suppressor of H. pylori induced stomach carcinogenesis.

Highlights

H. pylori infection is considered the main risk factor for gastric cancer [1,2,3]
WT mice infected with H. pylori, with CagA antibody and there was no difference in the number of CagA positive H. pylori between L22P versus WT mice stomach (Figure 1A)
L22P mutation increases cell proliferation in gastric cells, we measured the level of ki-67 positive cells with immunohistochemistry staining and we found that the percent of ki-67 positive cells significantly increased in L22P versus WT mice infected with H. pylori (Figure 1F,G; p < 0.05)

Summary

Introduction

H. pylori infection is considered the main risk factor for gastric cancer [1,2,3]. In this case, the predisposing inflammation is most often caused by colonization of the gastric epithelium by Helicobacter pylori (H. pylori) and chronically infected individuals have an increased risk of developing gastric cancer [3,4]. H. pylori associated chronic inflammation induces immune and epithelial cells to release reactive oxygen and nitrogen species (RONS), which are capable of causing DNA damage [5,6]. H. pylori infection inhibits DNA repair proteins, including mismatch repair proteins and base excision repair (BER)

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