Modification of Helicobacter pylori peptidoglycan enhances NOD1 activation and promotes cancer of the stomach

Suarez, Giovanni; Romero-Gallo, Judith; Piazuelo, M. Blanca; Wang, Ge; Maier, Robert J.; Forsberg, Lennart S.; Azadi, Parastoo; Gomez, Martin A.; Correa, Pelayo; Peek, Jr., Richard M.

doi:10.1158/0008-5472.can-14-2291

Modification of Helicobacter pylori peptidoglycan enhances NOD1 activation and promotes cancer of the stomach

Journal Article · Mon Mar 02 00:00:00 EST 2015 · Cancer Research

DOI:https://doi.org/10.1158/0008-5472.can-14-2291· OSTI ID:1345502

Suarez, Giovanni ^[1]; Romero-Gallo, Judith ^[2]; Piazuelo, M. Blanca ^[2]; Wang, Ge ^[3]; Maier, Robert J. ^[3]; Forsberg, Lennart S. ^[3]; Azadi, Parastoo ^[3]; Gomez, Martin A. ^[4]; Correa, Pelayo ^[2]; Peek, Jr., Richard M. ^[2]

Vanderbilt Univ., Nashville, TN (United States); DOE Office of Scientific and Technical Information (OSTI)
Vanderbilt Univ., Nashville, TN (United States)
Univ. of Georgia, Athens, GA (United States)
National Univ. of Colombia, Bogota (Colombia); Hospital El Tunal Unit of Gastroenterology, Bogota (Colombia)

Helicobacter pylori is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan (PGN) into host cells. NOD1 is an intracellular immune receptor that senses PGN from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering PGN structure. We previously demonstrated that the H. pylori cag⁺ strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Co-culture of H. pylori strain 7.13 or its pgdA^$$-$$ isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA^$$-$$ mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, pre-activation of NOD1 prior to bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared to non-cancer samples harvested from the same patients. In conclusion, these results indicate that PGN deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Georgia, Athens, GA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: FG02-93ER20097

OSTI ID:: 1345502

Journal Information:: Cancer Research, Journal Name: Cancer Research Journal Issue: 8 Vol. 75; ISSN 0008-5472

Publisher:: American Association for Cancer ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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