The Role of TLR2, TLR4 and CD14 Genetic Polymorphisms in Gastric Carcinogenesis: A Case-Control Study and Meta-Analysis

Castaño-Rodríguez, Natalia; Kaakoush, Nadeem O.; Goh, Khean‐Lee; Fock, Kwong Ming; Mitchell, Hazel M.

doi:10.1371/journal.pone.0060327

Cited by 68 publications

(59 citation statements)

References 64 publications

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“…Recently, the innate immune response to H. pylori was revealed to be an important factor affecting gastric mucosal inflammation (8,20). The present study previously reported a significant association between the TLR2-196 to -174 deletion polymorphism and gastric cancer susceptibility in Japanese patients (21), which was consistent with other Japanese studies associating TLR gene polymorphisms to gastric cancer (14). NOD2 polymorphisms are also associated with changes in gastric mucosa, which lead to gastric cancer susceptibility (13,22,23).…”

Section: Discussionsupporting

confidence: 91%

“…Single nucleotide polymorphisms (SNPs) of the receptor interacting serine/threonine kinase 2 (RIPK2) gene, encoding RIP2, are associated with systemic lupus erythematosus (SLE) (11), and with the severity of childhood atopic asthma (12). However, although the association of NOD2 and TLR polymorphisms with gastric cancer susceptibility have been described, RIPK2 polymorphisms have not been studied in this context (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Association between receptor interacting serine/threonine kinase 2 polymorphisms and gastric cancer susceptibility

et al. 2018

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Association between receptor interacting serine/threonine kinase 2 polymorphisms and gastric cancer susceptibility

et al. 2018

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“…TLR2 and TLR4 have been demonstrated to be important for the homeostasis of intestinal epithelial cells (39), and polymorphisms of TLR2 and TLR4 have been shown to be associated with an increased risk of gastric cancer (40,41). Accordingly, TLR2 or TLR4 are important candidates for responsible TLRs in gastric tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Maeda

Echizen

Oshima

et al. 2016

Cancer Prevention Research

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It has been established that COX-2 and downstream signaling by prostaglandin E 2 (PGE 2 ) play a key role in tumorigenesis through generation of inflammatory microenvironment. Tolllike receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE 2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE 2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE 2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE 2 pathway will be an effective preventive strategy for gastric cancer.Cancer Prev Res; 9(3); 253-63. Ó2016 AACR.

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“…For H. pylori infection, TLRs on gastric epithelia and immune cells recognize diverse pathogen-associated molecular patterns (PAMPs) such as flagellin, unmethylated CpG motifs and lipopolysaccharides (LPS) (28). For example, in addition to monocyte differentiation antigen (CD14) and myeloid differentiation protein (MD-2), TLR4 can interact with LPS, and this interaction induces signal transduction pathways that activate NF-κB and cause the expression of several cytokines, including TNF-α, IL-1β, IL-6 and IL-12 (29). Additionally, TLR2 induces cell proliferation and TLR4 activation expression via the MEK1/2-ERK/2 pathway (13,30).…”

Section: Discussionmentioning

confidence: 99%

“…However, conflicting data concerning their role in GC development have been reported. For example, a 22-bp nucleotide deletion in the promoter region of TLR2 (196 to 174) has been shown to either increase or decrease the risk of GC, depending on racial differences, increasing the GC risk approximately 6.06-fold in a Japanese population but decreasing the GC risk approximately 0.66-fold in a Chinese population (29). Additionally, TLR2 rs3804099 and rs3804100 were not significantly associated with decreased risk of H. pylori susceptibility, precancerous gastric lesions and/or GC development in this study.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptors are Associated with Helicobacter pylori Infection and Gastric Mucosa Pathology

Simawaranon

Wattanawongdon

Tongtawee

2017

Jundishapur J Microbiol

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Background: Toll-like receptors (TLRs) mediate recognition of Helicobacter pylori and initiate the innate immune response to infection. Toll-like receptors polymorphisms are thought to influence susceptibility to H. pylori infection and H. pylori-related diseases. Objectives: To investigate the association of TLR polymorphisms with the susceptibility to H. pylori infection and various types of gastritis in Thai patients. Methods: The single nucleotide polymorphisms (SNPs) TLR1 rs4833095, TLR2 rs3804099 and rs3804100, TLR4 rs10759932 and TLR10 rs10004195 were analysed in 400 gastritis patients by real-time PCR using a TaqMan SNP Genotyping Assay. The association between TLR polymorphisms and the risk of H. pylori infection was investigated in 196 uninfected and 204 H. pylori-infected patients. The associations between TLR genotypes and the risk of gastric pathology changes, including chronic gastritis (N = 312 cases) and precancerous gastric lesions/gastric cancer (GC) (N = 88 cases), were examined. Univariate analysis was used to determine odds ratios (ORs) with confidence intervals (95% CIs). Results: Patients with the CC -or TT homozygous genotype for TLR1 rs4833095 had a significantly increased risk of H. pylori susceptibility (OR = 2.28, 95% CI = 1.27 -7.60, P = 0.02 and OR = 1.34, 95% CI = 0.97 -1.86, P = 0.04, respectively). Patients with the AA homozygous genotype for TLR10 rs10004195 had a significantly increased risk of H. pylori susceptibility (OR = 1.28, 95% CI = 0.98 -1.76, P = 0.01) and exhibited a significantly increased risk of precancerous gastric lesions/GC (OR = 8.75, 95% CI = 2.78 -14.24, P < 0.01). Conclusions: Our findings suggest that the TLR1 rs4833095 and TLR10 rs10004195 polymorphisms are potential genetic risk factors that modify the H. pylori infection susceptibility and influence the clinical manifestation of chronic gastritis, precancerous gastric lesions and GC in Thai patients.

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The Role of TLR2, TLR4 and CD14 Genetic Polymorphisms in Gastric Carcinogenesis: A Case-Control Study and Meta-Analysis

Cited by 68 publications

References 64 publications

Association between receptor interacting serine/threonine kinase 2 polymorphisms and gastric cancer susceptibility

Association between receptor interacting serine/threonine kinase 2 polymorphisms and gastric cancer susceptibility

Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment

Toll-Like Receptors are Associated with Helicobacter pylori Infection and Gastric Mucosa Pathology

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