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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

  • Research Article
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Tumor Biology

Abstract

Toll-like receptors (TLRs) are considered as major endotoxin-signaling receptor and as crucial sensors of innate immunity. TLRs recognize pathogen-associated molecular patterns; induce effectors genes involving inflammatory cytokines and therefore initiation of adaptative immune responses against pathogens. Recently, it has been shown that TLRs are involved in tumor progression. In fact, increased level of TLR4 is associated with progression of colon malignancies. Even, TLR4 polymorphism has been shown associated with susceptibility to have colorectal cancer. Our study aimed to investigate an association between TLR4 Asp299Gly (D299G) and Thr399Ile (T399I) polymorphisms in Tunisian patients with colorectal cancer. Using a primer extension method (SNaPshot), we genotyped two variants of TLR4 D299G and T399I in 100 patients with colorectal cancer and 140 healthy controls in Tunisian population. Interesting, we noted a significant association between T399I polymorphism and tumor differentiation (p = 0.027) and tumor architecture (p = 0.02) in colorectal cancer (CRC) patients. We also showed a significant association of D299G with an increased risk of advanced stage (p = 0.03). Finally, we observed a positive link between D299G and T399I polymorphisms and CRC patients with lymph node (p = 0.00024; p = 0.0005, respectively) and metastasis (p = 0.001; p = 0.002, respectively). However, we found no evidence to support a significant association between TLR4 D299G and T399I polymorphisms and colorectal cancer susceptibility. Our findings suggest that TLR4 D299G and T399I polymorphisms are significantly associated with clinical features variables. TLR4 polymorphisms may serve as biomarker of disease progression. Therefore, our results need confirmation in even larger studies.

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Abbreviations

TLR:

Toll-like receptor

PRR:

Pathogen recognition receptors

PAMPs:

Pathogen-associated molecular patterns

LPS:

Lipopolysaccharide

CRC:

Colorectal cancer

CD:

Crohn’s disease

UC:

Ulcerative colitis

CAC:

Colitis-associated cancer

MyD88:

Myeloid differentiation factor 88

NF-κB:

Nuclear factor κB

TNFα:

Tumor necrosis factor α

TIRAP:

Toll-interleukin 1 receptor (TIR) domain containing adaptor protein

TRIF:

TIR domain-containing adaptor protein inducing interferon-β

TRAM:

Toll-like receptor adaptor molecule 2

IL1/6:

Interleukin 1/6

TNM stage:

Tumor node metastasis stage

EGFR:

Epidermal growth factor receptor

Cox-2:

Cyclooxygenase 2

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Acknowledgments

We would like to thank all the members of “Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont Ferrand, France” for their technical assistance.

Conflicts of interest

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Authors and Affiliations

  1. Laboratoire de Génétique Immunologie et Pathologie Humaine, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Tunis, 2092, Tunisia

    Ines Omrane, Olfa Baroudi, Imen Medimegh, Hager Ayari, Nejla Stambouli, Hssan Bouzayenne, Raja Marrakchi, Amel Benammar-Elgaaid & Karim Bougatef

  2. Service d’anatomie et de cytologie pathologique de l’Hôpital Charles Nicolle de Tunis, Tunis, Tunisia

    Nadia Kourda

  3. Laboratoire de Diagnostique Génétique et Moléculaire, Centre Jean Perrin, Clermont Ferrand, France

    Yves-Jean Bignon, Nancy Uhrhammer & Alexis Desrichard

  4. Service d’oncologie médicale de l’institut Salah Azaiez de Tunis, Tunis, Tunisia

    Amel Mezlini

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  1. Ines Omrane
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  2. Olfa Baroudi
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Correspondence to Ines Omrane.

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Omrane, I., Baroudi, O., Kourda, N. et al. Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis. Tumor Biol. 35, 545–551 (2014). https://doi.org/10.1007/s13277-013-1075-6

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  • DOI: https://doi.org/10.1007/s13277-013-1075-6

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