title: The NOD-like receptor signalling pathway in Helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses.
abstract: 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).
  
  
  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.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Castaño-Rodríguez
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Nadeem O
authors.initials: NO
authors.lastname: Kaakoush
authors.affiliation: Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Khean-Lee
authors.initials: KL
authors.lastname: Goh
authors.affiliation: Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore, Singapore.
authors.forename: Kwong Ming
authors.initials: KM
authors.lastname: Fock
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D002460:Cell Line; D002681:China; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D016480:Helicobacter pylori; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051192:Receptors, Pattern Recognition