Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis

Omrane, Ines; Baroudi, Olfa; Kourda, Nadia; Bignon, Yves‐Jean; Uhrhammer, Nancy; Desrichard, Alexis; Medimegh, Imen; Ayari, Hager; Stambouli, Nejla; Mézlini, Amel; Bouzayenne, Hssan; Marrakchi, Raja; Benammar-Elgaaid, Amel; Bougatef, Karim

doi:10.1007/s13277-013-1075-6

Cited by 31 publications

(26 citation statements)

References 37 publications

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“…Furthermore, the peritumoural immune reaction and tumour budding at the invasive front have a profound effect on survival in CRC. Functional polymorphisms of TLR2 and -4 show association with the risk and features of CRC, such as differentiation, advanced stage, lymph node status, and metastasis, and also affect expression levels[26,27]. Accordingly, occurrence of TLR polymorphisms may contribute to contradictory results of expression analyses and warrant further studies.…”

Section: Discussionmentioning

confidence: 99%

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Paarnio¹,

Väyrynen²,

Klintrup³

et al. 2017

WJG

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AIMTo characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa.METHODSWe analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed.RESULTSNormal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours.CONCLUSIONTumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Paarnio¹,

Väyrynen²,

Klintrup³

et al. 2017

WJG

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“…The detection of these two SNPs was carried out using allele-specific polymerase chain reaction and the primer extension method (SNaPshot) for gastric cancer and CRC, respectively. For gastric cancer, only Thr399Ile showed a significant correlation, while both the SNPs were significantly correlated to CRC (94, 100, 101). In addition, the association of the TLR3 (rs3775291) polymorphism and IL-10 promoter variation (rs1800872) to CRC pathogenesis was evaluated in a large cohort of German CRC patients.…”

Section: Correlation Between Crc Development and Inherited Genetic Vamentioning

confidence: 94%

“…Besides CRC, many human pathologies and carcinomas are associated with the polymorphisms of TLR4 (91–93). The TLR4 gene contains two single-nucleotide polymorphisms (SNPs), namely, Asp299Gly and Thr399Ile that are significantly important in tumor development (94, 95). Both these SNPs are located in the coding sequence for the TLR4 ectodomain and mediate an amino acid substitution.…”

Section: Correlation Between Crc Development and Inherited Genetic Vamentioning

confidence: 99%

“…Both these SNPs are located in the coding sequence for the TLR4 ectodomain and mediate an amino acid substitution. These Asp299Gly and Thr399Ile SNPs in TLR4 are known to attenuate cytokine expression, leading to an increased propensity for the development of gastric cancer and CRC (94, 96–99). The detection of these two SNPs was carried out using allele-specific polymerase chain reaction and the primer extension method (SNaPshot) for gastric cancer and CRC, respectively.…”

Section: Correlation Between Crc Development and Inherited Genetic Vamentioning

confidence: 99%

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Multiple Roles of Toll-Like Receptor 4 in Colorectal Cancer

et al. 2014

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Toll-like receptor (TLR) signaling has been implicated in the inflammatory responses in intestinal epithelial cells (IECs). Such inflammatory signals mediate complex interactions between commensal bacteria and TLRs and are required for IEC proliferation, immune response, repair, and homeostasis. The upregulation of certain TLRs in colorectal cancer (CRC) tissues suggests that TLRs may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in CRC. Here, we provide a comprehensive review of the literature on the involvement of the TLR pathway in the initiation, progression, and metastasis of CRC, as well as inherited genetic variation and epigenetic regulation. The differential expression of TLRs in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in CRC development and pathogenesis, and propose novel and promising approaches for CRC therapeutics with the aid of TLR ligands.

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“…The human TLR-4 gene is located in chromosomal region 9 (9q32-q33) and consists of four exons and three introns with an overall length of approximately 19 kb [9]. As one of the most actively investigated TLR, TLR-4 has been implicated in signal transduction events induced by the lipopolysaccharide of gram-negative bacteria and its activation in the production of several pro-inflammatory, antiviral and anti-bacterial cytokines [10], [11]. Since TLR-4 is critical in immune and inflammation responses to various bacteria in the intestine [12], single nucleotide polymorphisms (SNPs) in TLR-4 may decrease the response to bacterial components, impact gut homeostasis, result in the impairment of TLRs activation, and thereby be conducive to the development of several inflammatory diseases including CRC [13], [14].…”

Section: Introductionmentioning

confidence: 99%

Role of Toll-Like Receptor 4 in Colorectal Carcinogenesis: A Meta-Analysis

Sun

et al. 2014

PLoS ONE

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ObjectiveThis meta-analysis was performed to evaluate the role of toll-like receptor 4 (TLR-4) in colorectal carcinogenesis.MethodsThe PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through November 1st, 2013 without language restrictions. Odds ratios (ORs) or standardized mean differences (SMD) with their 95% confidence intervals (CI) were calculated.ResultsFourteen case-control studies met the inclusion criteria for this meta-analysis. A total of 1,209 colorectal cancer (CRC) cases and 1,218 healthy controls were involved in this meta-analysis. Two common polymorphisms (299 A>G and 399 C>T) in the TLR-4 gene, TLR-4 mRNA and protein expression were assessed. Our meta-analysis results revealed that the TLR-4 399 C>T polymorphism might increase the risk of CRC (allele model: OR = 1.77, 95%CI = 1.32∼2.36, P<0.001; dominant model: OR = 1.83, 95%CI = 1.32∼2.52, P<0.001; respectively). However, we found no correlation between the TLR-4 299 A>G polymorphism and CRC risk (all P>0.05). A subgroup analysis by ethnicity suggested that TLR-4 genetic polymorphisms were associated with an increased risk of CRC among Asians (allele model: OR = 1.50, 95%CI = 1.19∼1.88, P = 0.001; dominant model: OR = 1.49, 95%CI = 1.16∼1.92, P = 0.002; respectively), but not among Caucasians and Africans (all P>0.05). Furthermore, our results showed that TLR-4 mRNA and protein levels in CRC patients were higher than those in healthy controls (TLR-4 mRNA: SMD = 2.51, 95%CI = 0.98∼4.05, P = 0.001; TLR-4 protein: OR = 4.75, 95%CI = 1.16∼19.36, P = 0.030; respectively).ConclusionOur findings provide empirical evidence that TLR-4 may play an important role in colorectal carcinogenesis. Thus, TLR-4 is a promising potential biomarker for the early diagnosis of CRC.

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Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis

Cited by 31 publications

References 37 publications

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer

Multiple Roles of Toll-Like Receptor 4 in Colorectal Cancer

Role of Toll-Like Receptor 4 in Colorectal Carcinogenesis: A Meta-Analysis

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