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bioRxiv · 10.1101/687962

NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

Sahan, A. Z.·Venkova, T.·Sayed, I. M.·Beswick, E.·Reyes, V.·Pinchuk, I.·Sahoo, D.·Ghosh, P.·Hazra, T. K.·Das, S.
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Abstract

The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; this response was more pronounced in Neil2 knockout (KO) mouse cells compared to wild type (WT) cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Interestingly, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. H. pylori-infected Neil2 KO mice showed higher inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of repair genes in gastric specimens showed the reduction of Neil2 level is linked to the GC progression. Taken together, our data suggest that down-regulation of NEIL2 is a plausible mechanism by which H. pylori infection derails DNA damage repair, amplifies the inflammatory response and initiates GCs.

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Sahan, A. Z., Venkova, T., Sayed, I. M., Beswick, E., Reyes, V., Pinchuk, I., Sahoo, D., Ghosh, P., Hazra, T. K., Das, S.. 2019-07-02. NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells. https://doi.org/10.1101/687962

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