Epigenetic Regulation of Tumor Suppressors by Helicobacter pylori Enhances EBV-Induced Proliferation of Gastric Epithelial Cells.

Saurabh Pandey,Hem Chandra Jha,Erle S Robertson,Sanket Kumar Shukla,Meghan K Shirley,Terence S Dermody

doi:10.1128/mbio.00649-18

Saurabh Pandey, Hem Chandra Jha + Show 4 more

Open Access

https://doi.org/10.1128/mbio.00649-18

Copy DOI

Journal: mBio	Publication Date: Apr 24, 2018
Citations: 34	License type: CC BY 4.0

Affiliation: University of Pennsylvania

Abstract

ABSTRACTHelicobacter pylori and Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association with H. pylori increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, H. pylori-EBV coinfection causes chronic inflammation in pediatric patients. We have established an H. pylori-EBV coinfection model system using human gastric epithelial cells. We showed that H. pylori infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by H. pylori stimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells.

Highlights

Helicobacter pylori functions together with Epstein-Barr virus (EBV) as a group 1 carcinogen which contributes to the development of gastric cancer (GC) [1, 2]
The first approach was that of simultaneous infection, where H. pylori and EBV were incubated simultaneously with the cells, and the second was that of sequential infection, where the gastric epithelial cells were first incubated with H. pylori and subjected to infection with EBV
We clustered the tumor suppressor genes (TSGs) into distinct functional classes, and, from that analysis, we showed that in vitro infection of the NCI-N87 gastric cells by H. pylori and EBV was associated with transcriptional repression of a number of cell cycle genes (APC, BRCA1, CDKN2A, FHIT, NEUROG1, phosphatase and tensin homologue (PTEN), RUNX3, TP73, and VHL), genes involved in apoptosis (BRCA1, CDKN2A, MGMT, PTEN, RUNX3, TP73, and VHL), and genes involved in DNA damage repair (APC, BRCA1, MGMT, and TP73) (Fig. 5B, C, and D) (Table S2)

Summary

Introduction

Helicobacter pylori functions together with Epstein-Barr virus (EBV) as a group 1 carcinogen which contributes to the development of gastric cancer (GC) [1, 2]. Epigenetic regulation of tumor suppressors by Helicobacter pylori enhances EBV-induced proliferation of gastric epithelial cells. Pathogens coexisting with host cells can act as effectors of gene regulation through epigenetic modifications. This impacts the overall etiology and pathogenesis associated with the respective disease. The periodontal bacterium Porphyromonas gingivalis can induce EBV reactivation through chromatin modification [11] This bacterium-virus synergy affects EBV-associated periodontal pathology [11]. H. pylori and EBV have been shown to impact epigenetic modifications of host cells [12, 13] This relationship, which exists within the microbial milieu and modulates host gene expression, can directly impact disease pathology

Methods

Results

Conclusion