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.

doi:10.1371/journal.pone.0098899

Cited by 103 publications

(83 citation statements)

References 57 publications

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“…An association of ATG16L1 polymorphisms with cancer has been observed in thyroid carcinoma, gastric cancer and oral squamous cell carcinoma and affects the outcome in colorectal cancer and lung cancer . Notably, the loss of function mutation p.T300A was protective in some but deleterious in other studies underlining that intact autophagy facilitates and suppresses tumorigenesis depending on the context.…”

Section: Discussionmentioning

confidence: 99%

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

Reuken

Lutz

Casper

et al. 2019

Liver International

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Background and aims: Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1β production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis. Methods:A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR.Results: The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis. Conclusion:The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis. K E Y W O R D S ATG16L1, autophagy, cirrhosis, genetic polymorphisms, hepatocellular carcinoma | 2361 REUKEN Et al.

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Section: Discussionmentioning

confidence: 99%

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

Reuken

Lutz

Casper

et al. 2019

Liver International

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“…NLRC3 is a biomarker for colorectal cancer [42]; NLRC4 was related to enterocolitis [43], recurrent macrophage activation syndrome [44], and familiar cold autoinflammatory syndrome [45]; and NLRC5 has been implicated in chronic periodontitis [46]. NLRX1 was found to be associated with risk of gastric cancer in the Chinese population [47]. Interestingly, the other four genes in the NLRC and NLRX gene families did not show any direct or indirect associations with HCC, with the exception of NOD1/NOD2 pathway, which acted synergistically with NLRP3.…”

Section: Discussionmentioning

confidence: 99%

NLRC and NLRX gene family mRNA expression and prognostic value in hepatocellular carcinoma

et al. 2017

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Nucleotide‐binding oligomerization domain (NOD)‐like receptor (NLR)C and NLRX family proteins play a key role in the innate immune response. The relationship between these proteins and hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic significance of NLRC and NLRX family protein levels in HCC patients. Data from 360 HCC patients in The Cancer Genome Atlas database and 231 patients in the Gene Expression Omnibus database were analyzed. Kaplan–Meier analysis and a Cox regression model were used to determine median survival time (MST) and overall and recurrence‐free survival by calculating the hazard ratio (HR) and 95% confidence interval (CI). High NOD2 and low NLRX1 expression in tumor tissue was associated with short MST (P = 0.012 and 0.014, respectively). A joint‐effects analysis of NOD2 and NLRX1 combined revealed that groups III and IV had reduced risk of death from HCC as compared to group I (adjusted P = 0.001, adjusted HR = 0.31, 95% CI = 0.16–0.61 and adjusted P = 0.043, adjusted HR = 0.63, 95%CI = 0.41–0.99, respectively). NOD2 and NLRX1 expression levels are potential prognostic markers in HCC following hepatectomy.

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“…Our gene expression analyses showed five genes encoding NLRs to be significantly regulated in H. pylori -challenged cells ( NLRC4, NLRC5, NLRP9, NLRP12 , and NLRX1 ) (173). Interestingly, NLRP12 and NLRX1 , two known NF-κB negative regulators, were markedly down-regulated, while NFKB1 and several NF-κB target genes encoding pro-inflammatory cytokines ( IFNB1, IL12A, IL-12B, IL6 , and TNF ), chemokines ( CXCL1, CXCL2 , and CCL5 ) and molecules involved in carcinogenesis ( PTGS2 and BIRC3 ) were markedly up-regulated, in THP-1 cells infected with a highly virulent H. pylori strain isolated from a GC patient.…”

Section: Nod-like Receptors and Helicobacter Pylori-related Gastric Cmentioning

confidence: 97%

Pattern-Recognition Receptors and Gastric Cancer

2014

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Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.

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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

Cited by 103 publications

References 57 publications

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis

NLRC and NLRX gene family mRNA expression and prognostic value in hepatocellular carcinoma

Pattern-Recognition Receptors and Gastric Cancer

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