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The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses
BACKGROUND: Currently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs) form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18). As chronic inflammation of the...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047072/ https://www.ncbi.nlm.nih.gov/pubmed/24901306 http://dx.doi.org/10.1371/journal.pone.0098899 |
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author | Castaño-Rodríguez, Natalia Kaakoush, Nadeem O. Goh, Khean-Lee Fock, Kwong Ming Mitchell, Hazel M. |
author_facet | Castaño-Rodríguez, Natalia Kaakoush, Nadeem O. Goh, Khean-Lee Fock, Kwong Ming Mitchell, Hazel M. |
author_sort | Castaño-Rodríguez, Natalia |
collection | PubMed |
description | BACKGROUND: Currently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs) form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18). As chronic inflammation of the gastric mucosa is a consequence of Helicobacter pylori infection, we investigated the role of genetic polymorphisms and expression of genes involved in the NLR signalling pathway in H. pylori infection and related gastric cancer (GC). MATERIALS AND METHODS: Fifty-one genetic polymorphisms were genotyped in 310 ethnic Chinese (87 non-cardia GC cases and 223 controls with functional dyspepsia). In addition, gene expression of 84 molecules involved in the NLR signalling pathway was assessed in THP-1 cells challenged with two H. pylori strains, GC026 (GC) and 26695 (gastritis). RESULTS: CARD8-rs11672725, NLRP3-rs10754558, NLRP3-rs4612666, NLRP12-rs199475867 and NLRX1-rs10790286 showed significant associations with GC. On multivariate analysis, CARD8-rs11672725 remained a risk factor (OR: 4.80, 95% CI: 1.39–16.58). Further, NLRP12-rs2866112 increased the risk of H. pylori infection (OR: 2.13, 95% CI: 1.22–3.71). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (CARD8, NLRP3, CASP1 and NLRP12 polymorphisms). In gene expression analyses, five genes encoding NLRs were significantly regulated in H. pylori-challenged cells (NLRC4, NLRC5, NLRP9, NLRP12 and NLRX1). Interestingly, persistent up-regulation of NFKB1 with simultaneous down-regulation of NLRP12 and NLRX1 was observed in H. pylori GC026-challenged cells. Further, NF-κB target genes encoding pro-inflammatory cytokines, chemokines and molecules involved in carcinogenesis were markedly up-regulated in H. pylori GC026-challenged cells. CONCLUSIONS: Novel associations between polymorphisms in the NLR signalling pathway (CARD8, NLRP3, NLRP12, NLRX1, and CASP1) and GC were identified in Chinese individuals. Our genetic polymorphisms and gene expression results highlight the relevance of the NLR signalling pathway in gastric carcinogenesis and its close interaction with NF-κB. |
format | Online Article Text |
id | pubmed-4047072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40470722014-06-09 The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses Castaño-Rodríguez, Natalia Kaakoush, Nadeem O. Goh, Khean-Lee Fock, Kwong Ming Mitchell, Hazel M. PLoS One Research Article BACKGROUND: Currently, it is well established that cancer arises in chronically inflamed tissue. A number of NOD-like receptors (NLRs) form inflammasomes, intracellular multiprotein complexes critical for generating mature pro-inflammatory cytokines (IL-1β and IL-18). As chronic inflammation of the gastric mucosa is a consequence of Helicobacter pylori infection, we investigated the role of genetic polymorphisms and expression of genes involved in the NLR signalling pathway in H. pylori infection and related gastric cancer (GC). MATERIALS AND METHODS: Fifty-one genetic polymorphisms were genotyped in 310 ethnic Chinese (87 non-cardia GC cases and 223 controls with functional dyspepsia). In addition, gene expression of 84 molecules involved in the NLR signalling pathway was assessed in THP-1 cells challenged with two H. pylori strains, GC026 (GC) and 26695 (gastritis). RESULTS: CARD8-rs11672725, NLRP3-rs10754558, NLRP3-rs4612666, NLRP12-rs199475867 and NLRX1-rs10790286 showed significant associations with GC. On multivariate analysis, CARD8-rs11672725 remained a risk factor (OR: 4.80, 95% CI: 1.39–16.58). Further, NLRP12-rs2866112 increased the risk of H. pylori infection (OR: 2.13, 95% CI: 1.22–3.71). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (CARD8, NLRP3, CASP1 and NLRP12 polymorphisms). In gene expression analyses, five genes encoding NLRs were significantly regulated in H. pylori-challenged cells (NLRC4, NLRC5, NLRP9, NLRP12 and NLRX1). Interestingly, persistent up-regulation of NFKB1 with simultaneous down-regulation of NLRP12 and NLRX1 was observed in H. pylori GC026-challenged cells. Further, NF-κB target genes encoding pro-inflammatory cytokines, chemokines and molecules involved in carcinogenesis were markedly up-regulated in H. pylori GC026-challenged cells. CONCLUSIONS: Novel associations between polymorphisms in the NLR signalling pathway (CARD8, NLRP3, NLRP12, NLRX1, and CASP1) and GC were identified in Chinese individuals. Our genetic polymorphisms and gene expression results highlight the relevance of the NLR signalling pathway in gastric carcinogenesis and its close interaction with NF-κB. Public Library of Science 2014-06-05 /pmc/articles/PMC4047072/ /pubmed/24901306 http://dx.doi.org/10.1371/journal.pone.0098899 Text en © 2014 Castaño-Rodríguez et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Castaño-Rodríguez, Natalia Kaakoush, Nadeem O. Goh, Khean-Lee Fock, Kwong Ming Mitchell, Hazel M. The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title | The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title_full | The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title_fullStr | The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title_full_unstemmed | The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title_short | The NOD-Like Receptor Signalling Pathway in Helicobacter pylori Infection and Related Gastric Cancer: A Case-Control Study and Gene Expression Analyses |
title_sort | nod-like receptor signalling pathway in helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047072/ https://www.ncbi.nlm.nih.gov/pubmed/24901306 http://dx.doi.org/10.1371/journal.pone.0098899 |
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