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.
| Original language | English (US) |
|---|---|
| Article number | 843 |
| Journal | Cancers |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 1 2019 |
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Keywords
- Gastric cancer
- Genomic instability
- H. pylori
- Mutation in DNA polymerase beta
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice. / Zhao, Shengyuan; Thakur, Megha; Klattenhoff, Alex W.; Kidane-Mulat, Dawit.
In: Cancers, Vol. 11, No. 6, 843, 01.06.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Aberrant DNA polymerase beta enhances H. Pylori infection induced genomic instability and gastric carcinogenesis in mice
AU - Zhao, Shengyuan
AU - Thakur, Megha
AU - Klattenhoff, Alex W.
AU - Kidane-Mulat, Dawit
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - Gastric cancer
KW - Genomic instability
KW - H. pylori
KW - Mutation in DNA polymerase beta
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U2 - 10.3390/cancers11060843
DO - 10.3390/cancers11060843
M3 - Article
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 6
M1 - 843
ER -