A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

Hold, Georgina L.; Rabkin, Charles S.; Chow, Wong‐Ho; Smith, M. G.; Gammon, Marilie D.; Risch, Harvey A.; Vaughan, Thomas L.; McColl, Kenneth E.L.; Lissowska, Jolanta; Zatoński, Witold; Schoenberg, Janet B.; Blot, William J.; Mowat, N. A. G.; Fraumeni, Joseph F.; El-Omar, Emad

doi:10.1053/j.gastro.2006.12.026

Cited by 242 publications

(206 citation statements)

References 40 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Sixteen percent of gastric cancer patients in the initial study and 15% of the non-cardia gastric cancer patients in the replication study had one or two TLR4 variant alleles vs 8% of both control populations (combined OR ¼ 2.4; 95% CI ¼ 1.6-3.4) (Hold et al, 2007). In contrast, prevalence of TLR4 þ 896G was not significantly increased in oesophageal squamous cell (2%, OR ¼ 0.4) or adenocarcinoma (9%, OR ¼ 0.8) or gastric cardia cancer (11%, OR ¼ 1.2) (Hold et al, 2007).…”

Section: H Pylori-induced Gastric Cancer Modelmentioning

confidence: 95%

“…TLR4 þ 896G carriers had a 7.7-fold (95% CI, 1.6-37.6) increased odds ratio (OR) for hypochlorhydria; the polymorphism was not associated with gastric acid output in the absence of H. pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation (Hold et al, 2007). Sixteen percent of gastric cancer patients in the initial study and 15% of the non-cardia gastric cancer patients in the replication study had one or two TLR4 variant alleles vs 8% of both control populations (combined OR ¼ 2.4; 95% CI ¼ 1.6-3.4) (Hold et al, 2007).…”

Section: H Pylori-induced Gastric Cancer Modelmentioning

confidence: 98%

“…SNP Asp299Gly was later shown to co-segregate with SNP Thr399Ile-also in the third exon of TLR4. Both SNPs are present in 10% of Caucasian populations and are reported to have a positive correlation with susceptibility to several infectious diseases (including gram-negative sepsis), atherosclerosis, asthma, malaria and also Helicobacter pylori-induced gastric cancer and its precursors (Mockenhaupt et al, 2006;Hold et al, 2007). However, neither SNP is present in Asian populations.…”

Section: Toll-like Receptormentioning

confidence: 99%

See 1 more Smart Citation

Polymorphisms in Toll-like receptor genes and risk of cancer

2008

View full text Add to dashboard Cite

“…A previous study has suggested that TLR4 Asp299Gly was associated with GC in Caucasians (26); but this polymorphism was not detected in Chinese patients (27)(28)(29). Moreover, although genetic polymorphisms of TLR5 have been characterized in the Caucasian population, no study was reported on its relationship with cancer susceptibility.…”

Section: Introductionmentioning

confidence: 95%

Genetic Variants of Toll-Like Receptor 2 and 5, Helicobacter Pylori Infection, and Risk of Gastric Cancer and Its Precursors in a Chinese Population

Zeng

Pan

Zhang

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Background: Genetic polymorphisms of Toll-like receptors (TLR) may influence the outcome of Helicobacter pylori infection and play important roles in gastric carcinogenesis. To screen the genetic variants of TLR2 and TLR5, and evaluate their associations with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, Shandong Province, China.Methods: Genetic variants were identified by PCR-based denaturing high-performance liquid chromatography and PCR-restriction fragment length polymorphism analysis in 248 GC cases, 846 subjects with advanced gastric lesions including 350 dysplasia and 496 intestinal metaplasia, and 496 superficial gastritis/mild chronic atrophic gastritis controls.Results: Nine allelic variants each were detected within the promoter and exons of TLR2 and TLR5. Among those, TLR2 c. À196 to À174 del carriers (ins/delþdel/del) showed a significantly decreased risk of GC (adjusted OR, 0.66; 95% CI: 0.48-0.90), whereas TLR5 rs5744174 C carriers (TCþCC) had an increased risk of GC (OR, 1.43; 95% CI: 1.03-1.97). Further analysis indicated an elevated risk of GC in subjects with the TLR5 rs5744174 TCþCC genotype and H. pylori infection (OR, 3.35; 95% CI: 2.13-5.26), and a significant interaction between rs5744174 and H. pylori infection was observed (OR, 2.15; 95% CI: 1.12-4.16).Conclusion: These findings suggest that TLR2 c. À196 to À174 ins>del, TLR5 rs5744174 and interaction between rs5744174 and H. pylori infection were associated with the development of GC.Impact: TLR2 and TLR5 polymorphisms may play important roles in the process of H. pylori-related gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 20(12); 2594-602. Ó2011 AACR.

show abstract

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

Abstract: Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

Cited by 242 publications

References 40 publications

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

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

Polymorphisms in Toll-like receptor genes and risk of cancer

Genetic Variants of Toll-Like Receptor 2 and 5, Helicobacter Pylori Infection, and Risk of Gastric Cancer and Its Precursors in a Chinese Population

Contact Info

Product

Resources

About