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7�% % �*% % % % % �?�?�*% % % �@% % % % ���������������������������������������������������������������������G% % % % % % % % % N$r:Involvement of TLR4 polymorphisms on colorectal cancer treatment 


Ines OMRANE1, Olfa BAROUDI1, Imen MEDIMEGH1, Hager AYARI1, Nadia KOURDA2, Amel MEZLINI3, Karim BOUGATEF1 and Amel BENAMMAR-ELGAAIED1 
1 Laboratoire de G�n�tique Immunologie et Pathologie Humaine, Facult� des Sciences de Tunis, Universit� de Tunis EL MANAR, Tunisie
2 Service d�anatomie et de cytologie pathologique de l�H�pital Charles Nicolle de Tunis, Tunisie

3 Service d�oncologie m�dicale de l�institut Salah Azaiez de Tunis, Tunisie



Correspondence�to In�s OMRANE, Laboratoire de G�n�tique Immunologie et Pathologie Humaine, Facult� des Sciences de Tunis El MANAR, Universit� EL MANAR, campus universitaire, Tunis 2092, Tunisie
E-mail�: HYPERLINK "mailto:inesomrane@hotmail.fr"inesomrane@hotmail.fr












Abstract 
It has been widely described the important role of polymorphisms on immunity genes in the susceptibility to various diseases. Both polymorphisms D299D and T399I of TLR4 are shown associated with inflammatory bowel diseases as well as colorectal cancer. Previously, we have shown that TLR4 polymorphisms are significantly associated with disease presentation of colorectal cancer such as late stage, differentiation as well as lymph, node and metastasis.  Our study aimed to investigate an association between TLR4 D299G and T399I polymorphisms in Tunisian patients with colorectal cancer treatment. We found that T399I and D299G polymorphism of TLR4 were significantly associated with adjuvant chemotherapy and radical surgery. We also showed that mutant alleles of T399I and D299G combined genotypes and haplotypes may affect the effectiveness of therapy. Finally, we showed no significant longer survival and TLR4 polymorphisms. In conclusion, we suggest that polymorphisms in TLR4 gene may be predictive of treatment type.
Keywords: colorectal cancer; treatment; chemotherapy; surgery; TLR4; polymorphisms


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Introduction
Transmembrane receptors TLR4 (Toll-like receptors) plays an important role in the innate immune response that allows the host defense against infectious diseases of bacterial origin.  Two missense mutations Asp299Gly (D299G) and Thr399IIe (T399I) were identified in the TLR4 gene, which result in an amino acid substitution in the third exon of the gene. These two mutations disrupt the extracellular region of the receptor at the site of binding with the ligand. Indeed, it has been shown that these two variants are associated with a reduced sensitivity to lipopolysccharides (LPS) and an attenuated immune response causing a decrease in the secretion of proinflammatory cytokines  ADDIN EN.CITE <EndNote><Cite><Author>Arbour</Author><Year>2000</Year><RecNum>42</RecNum><record><rec-number>42</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arbour, N. C.</author><author>Lorenz, E.</author><author>Schutte, B. C.</author><author>Zabner, J.</author><author>Kline, J. N.</author><author>Jones, M.</author><author>Frees, K.</author><author>Watt, J. L.</author><author>Schwartz, D. A.</author></authors></contributors><auth-address>[1] Department of Medicine, Department of Veterans Affairs Medical Center, The University of Iowa, Iowa City, Iowa, USA.</auth-address><titles><title>TLR4 mutations are associated with endotoxin hyporesponsiveness in humans</title><secondary-title>Nat Genet</secondary-title><alt-title>Nature genetics</alt-title></titles><periodical><full-title>Nat Genet</full-title><abbr-1>Nature genetics</abbr-1></periodical><alt-periodical><full-title>Nat Genet</full-title><abbr-1>Nature genetics</abbr-1></alt-periodical><pages>187-91</pages><volume>25</volume><number>2</number><keywords><keyword>Administration, Inhalation</keyword><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Alleles</keyword><keyword>Amino Acid Sequence</keyword><keyword>Base Sequence</keyword><keyword>Cells, Cultured</keyword><keyword>DNA Mutational Analysis</keyword><keyword>*Drosophila Proteins</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume/drug effects</keyword><keyword>Humans</keyword><keyword>Lipopolysaccharides/administration &amp; dosage/*pharmacology</keyword><keyword>Macrophages, Alveolar/drug effects/*physiology</keyword><keyword>Male</keyword><keyword>Membrane Glycoproteins/chemistry/*genetics/metabolism</keyword><keyword>Middle Aged</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation, Missense/*genetics</keyword><keyword>Receptors, Cell Surface/chemistry/*genetics/metabolism</keyword><keyword>Respiratory Hypersensitivity/chemically induced/genetics/physiopathology</keyword><keyword>Respiratory Mucosa/drug effects/*physiology</keyword><keyword>Signal Transduction/drug effects</keyword><keyword>Toll-Like Receptor 4</keyword><keyword>Toll-Like Receptors</keyword></keywords><dates><year>2000</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1061-4036 (Print)&#xD;1061-4036 (Linking)</isbn><accession-num>10835634</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=10835634 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[1]. 
In fact, both D299G and T399I polymorphisms are shown associated with inflammatory bowel disease (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC)  ADDIN EN.CITE <EndNote><Cite><Author>Shen</Author><Year>2010</Year><RecNum>1</RecNum><record><rec-number>1</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shen, X.</author><author>Shi, R.</author><author>Zhang, H.</author><author>Li, K.</author><author>Zhao, Y.</author><author>Zhang, R.</author></authors></contributors><auth-address>Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.</auth-address><titles><title>The Toll-like receptor 4 D299G and T399I polymorphisms are associated with Crohn&apos;s disease and ulcerative colitis: a meta-analysis</title><secondary-title>Digestion</secondary-title><alt-title>Digestion</alt-title></titles><periodical><full-title>Digestion</full-title><abbr-1>Digestion</abbr-1></periodical><alt-periodical><full-title>Digestion</full-title><abbr-1>Digestion</abbr-1></alt-periodical><pages>69-77</pages><volume>81</volume><number>2</number><keywords><keyword>Alleles</keyword><keyword>Colitis, Ulcerative/ethnology/*genetics</keyword><keyword>Crohn Disease/ethnology/*genetics</keyword><keyword>*European Continental Ancestry Group</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Phenotype</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword></keywords><dates><year>2010</year></dates><isbn>1421-9867 (Electronic)&#xD;0012-2823 (Linking)</isbn><accession-num>20093834</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=20093834 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[2] and increase the risk of some cancers such as breast cancer, gastric cancer and colorectal cancer  ADDIN EN.CITE <EndNote><Cite><Author>Hold</Author><Year>2007</Year><RecNum>6</RecNum><record><rec-number>6</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hold, G. L.</author><author>Rabkin, C. S.</author><author>Chow, W. H.</author><author>Smith, M. G.</author><author>Gammon, M. D.</author><author>Risch, H. A.</author><author>Vaughan, T. L.</author><author>McColl, K. E.</author><author>Lissowska, J.</author><author>Zatonski, W.</author><author>Schoenberg, J. B.</author><author>Blot, W. J.</author><author>Mowat, N. A.</author><author>Fraumeni, J. F., Jr.</author><author>El-Omar, E. M.</author></authors></contributors><auth-address>Department of Medicine and Therapeutics, Aberdeen University, Aberdeen, Scotland.</auth-address><titles><title>A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></periodical><alt-periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></alt-periodical><pages>905-12</pages><volume>132</volume><number>3</number><keywords><keyword>Achlorhydria/genetics/microbiology</keyword><keyword>Carcinoma/*genetics/microbiology/pathology</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Europe</keyword><keyword>Female</keyword><keyword>Gastritis, Atrophic/genetics/microbiology</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>Gene Frequency</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genotype</keyword><keyword>Helicobacter Infections/complications/genetics/*microbiology</keyword><keyword>*Helicobacter pylori</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Odds Ratio</keyword><keyword>Phenotype</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Population Surveillance</keyword><keyword>Precancerous Conditions/*genetics/microbiology/pathology</keyword><keyword>Registries</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Stomach Neoplasms/*genetics/microbiology/pathology</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword><keyword>United States</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>17324405</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17324405 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Theodoropoulos</Author><Year>2012</Year><RecNum>4</RecNum><record><rec-number>4</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Theodoropoulos, G. E.</author><author>Saridakis, V.</author><author>Karantanos, T.</author><author>Michalopoulos, N. V.</author><author>Zagouri, F.</author><author>Kontogianni, P.</author><author>Lymperi, M.</author><author>Gazouli, M.</author><author>Zografos, G. C.</author></authors></contributors><auth-address>First Propaedeutic Surgical Dept, School of Medicine, Hippocratio General Hospital, Athens, Greece.</auth-address><titles><title>Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development</title><secondary-title>Breast</secondary-title><alt-title>Breast (Edinburgh, Scotland)</alt-title></titles><periodical><full-title>Breast</full-title><abbr-1>Breast (Edinburgh, Scotland)</abbr-1></periodical><alt-periodical><full-title>Breast</full-title><abbr-1>Breast (Edinburgh, Scotland)</abbr-1></alt-periodical><pages>534-8</pages><volume>21</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Amplified Fragment Length Polymorphism Analysis</keyword><keyword>Base Sequence</keyword><keyword>Breast Neoplasms/*genetics</keyword><keyword>Case-Control Studies</keyword><keyword>Female</keyword><keyword>Gene Frequency</keyword><keyword>Genetic Markers</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Genotyping Techniques</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>*Polymorphism, Single Nucleotide</keyword><keyword>Sequence Deletion</keyword><keyword>Toll-Like Receptor 2/*genetics</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1532-3080 (Electronic)&#xD;0960-9776 (Linking)</isbn><accession-num>22560646</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=22560646 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Pimentel-Nunes</Author><Year>2010</Year><RecNum>3</RecNum><record><rec-number>3</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Pimentel-Nunes, P.</author><author>Teixeira, A. L.</author><author>Pereira, C.</author><author>Gomes, M.</author><author>Brandao, C.</author><author>Rodrigues, C.</author><author>Goncalves, N.</author><author>Boal-Carvalho, I.</author><author>Roncon-Albuquerque, R., Jr.</author><author>Moreira-Dias, L.</author><author>Leite-Moreira, A. F.</author><author>Medeiros, R.</author><author>Dinis-Ribeiro, M.</author></authors></contributors><auth-address>Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research &amp; Development Unit, Faculty of Medicine, University of Porto, Portugal. pedronunesml@gmail.com</auth-address><titles><title>Functional polymorphisms of Toll-like receptors 2 and 4 alter the risk for colorectal carcinoma in Europeans</title><secondary-title>Dig Liver Dis</secondary-title></titles><periodical><full-title>Dig Liver Dis</full-title></periodical><pages>63-9</pages><volume>45</volume><number>1</number><dates><year>2010</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1878-3562 (Electronic)&#xD;1590-8658 (Linking)</isbn><accession-num>22999059</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=22999059 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[3-5]. However, in our previous study, we have shown no significant association between D299G and T399I polymorphisms and the incidence of colorectal cancer in the Tunisian population  ADDIN EN.CITE <EndNote><Cite><Author>Omrane</Author><RecNum>5</RecNum><record><rec-number>5</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Omrane, I.</author><author>Baroudi, O.</author><author>Bougatef, K.</author><author>Mezlini, A.</author><author>Abidi, A.</author><author>Medimegh, I.</author><author>Stambouli, N.</author><author>Ayari, H.</author><author>Kourda, N.</author><author>Uhrhammer, N.</author><author>Bignon, Y. J.</author><author>Benammar Elgaaied, A.</author><author>Marrakchi, R.</author></authors></contributors><auth-address>Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia. Electronic address: inesomrane@hotmail.fr.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Gastroenterology Service, Salah Azaiez hospital of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Anatomy and Pathology, Charles Nicolle Hospital of Tunis, Tunisia.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.</auth-address><titles><title>Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer</title><secondary-title>Immunol Lett</secondary-title><alt-title>Immunology letters</alt-title></titles><periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></periodical><alt-periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></alt-periodical><pages>189-94</pages><volume>158</volume><number>1-2</number><dates><year>2014</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1879-0542 (Electronic)&#xD;0165-2478 (Linking)</isbn><accession-num>24440568</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=24440568 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[6].
In addition to the role of TLR4 polymorphisms in colorectal cancer, these mutations are also involved in the presentation of this disease. In fact, D299G and T399I are significantly associated with clinical features such as differentiation and architecture of the tumor and with advanced stage of the colorectal cancer. Moreover, it has been shown that these polymorphisms present a risk factor to lymph node and metastasis in patients with colorectal cancer  ADDIN EN.CITE <EndNote><Cite><Author>Omrane</Author><RecNum>5</RecNum><record><rec-number>5</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Omrane, I.</author><author>Baroudi, O.</author><author>Bougatef, K.</author><author>Mezlini, A.</author><author>Abidi, A.</author><author>Medimegh, I.</author><author>Stambouli, N.</author><author>Ayari, H.</author><author>Kourda, N.</author><author>Uhrhammer, N.</author><author>Bignon, Y. J.</author><author>Benammar Elgaaied, A.</author><author>Marrakchi, R.</author></authors></contributors><auth-address>Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia. Electronic address: inesomrane@hotmail.fr.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Gastroenterology Service, Salah Azaiez hospital of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Anatomy and Pathology, Charles Nicolle Hospital of Tunis, Tunisia.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.</auth-address><titles><title>Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer</title><secondary-title>Immunol Lett</secondary-title><alt-title>Immunology letters</alt-title></titles><periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></periodical><alt-periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></alt-periodical><pages>189-94</pages><volume>158</volume><number>1-2</number><dates><year>2014</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1879-0542 (Electronic)&#xD;0165-2478 (Linking)</isbn><accession-num>24440568</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=24440568 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Eyking</Author><Year>2011</Year><RecNum>6</RecNum><record><rec-number>6</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Eyking, A.</author><author>Ey, B.</author><author>Runzi, M.</author><author>Roig, A. I.</author><author>Reis, H.</author><author>Schmid, K. W.</author><author>Gerken, G.</author><author>Podolsky, D. K.</author><author>Cario, E.</author></authors></contributors><auth-address>Division of Gastroenterology &amp; Hepatology, University Hospital of Essen, Medical School, University of Duisburg-Essen, Essen, Germany.</auth-address><titles><title>Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></periodical><alt-periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></alt-periodical><pages>2154-65</pages><volume>141</volume><number>6</number><keywords><keyword>Adenocarcinoma/genetics/metabolism/*pathology</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Animals</keyword><keyword>Caco-2 Cells</keyword><keyword>Colonic Neoplasms/genetics/metabolism/*pathology</keyword><keyword>*Disease Progression</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Epithelial-Mesenchymal Transition</keyword><keyword>Female</keyword><keyword>Gene Expression Profiling</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Immunoblotting</keyword><keyword>Inflammation/immunology</keyword><keyword>Intestinal Mucosa/*drug effects</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Microscopy, Fluorescence</keyword><keyword>Middle Aged</keyword><keyword>Oligonucleotide Array Sequence Analysis</keyword><keyword>RNA, Messenger/genetics</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction</keyword><keyword>STAT3 Transcription Factor/metabolism</keyword><keyword>Toll-Like Receptor 4/*physiology</keyword><keyword>Wnt Signaling Pathway</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1528-0012 (Electronic)&#xD;0016-5085 (Linking)</isbn><accession-num>21920464</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21920464 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Simiantonaki</Author><Year>2007</Year><RecNum>27</RecNum><record><rec-number>27</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simiantonaki, N.</author><author>Kurzik-Dumke, U.</author><author>Karyofylli, G.</author><author>Jayasinghe, C.</author><author>Michel-Schmidt, R.</author><author>Kirkpatrick, C. J.</author></authors></contributors><auth-address>Institute of Pathology, Johannes Gutenberg University, Mainz, Germany. simiantonaki@klinikum-lev.de</auth-address><titles><title>Reduced expression of TLR4 is associated with the metastatic status of human colorectal cancer</title><secondary-title>Int J Mol Med</secondary-title><alt-title>International journal of molecular medicine</alt-title></titles><periodical><full-title>Int J Mol Med</full-title><abbr-1>International journal of molecular medicine</abbr-1></periodical><alt-periodical><full-title>Int J Mol Med</full-title><abbr-1>International journal of molecular medicine</abbr-1></alt-periodical><pages>21-9</pages><volume>20</volume><number>1</number><keywords><keyword>Antigens, CD14/metabolism</keyword><keyword>Caco-2 Cells</keyword><keyword>Carcinoma/*pathology/surgery</keyword><keyword>Cell Line, Tumor</keyword><keyword>Colorectal Neoplasms/*pathology/surgery</keyword><keyword>Fluorescent Antibody Technique, Indirect</keyword><keyword>*Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Lipopolysaccharides/*metabolism/pharmacology</keyword><keyword>Lymphatic Metastasis/pathology</keyword><keyword>Neoplasm Metastasis/pathology</keyword><keyword>Neoplasm Staging</keyword><keyword>Retrospective Studies</keyword><keyword>Toll-Like Receptor 4/genetics/*metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1107-3756 (Print)&#xD;1107-3756 (Linking)</isbn><accession-num>17549384</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17549384 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[6-8].
Colorectal cancer is considered as the major cause of mortality and morbidity in the world.  In Tunisia, colorectal cancer is the first digestive cancer with nearly 40% of cases occurring after 60 years with a male predominance. It occupies the fourth rank in males after lung, bladder and prostate cancers, and the second in women after breast cancer. Surgery is the main treatment for colorectal cancer. The procedure involves the resection of the affected segment of colon with healthy margins colon. Moreover, in case of delay in diagnosis, colorectal cancer is locally advanced and total resection becomes impossible  ADDIN EN.CITE <EndNote><Cite><Author>Lelong</Author><Year>2004</Year><RecNum>8</RecNum><record><rec-number>8</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lelong, B.</author><author>Moutardier, V.</author><author>Delpero, J. R.</author></authors></contributors><auth-address>Departement de chirurgie oncologique, Institut Paoli-Calmettes, 13273 Marseille 9.</auth-address><titles><title>[Colorectal cancer: what should be the management of primary tumour?]</title><secondary-title>Rev Prat</secondary-title><alt-title>La Revue du praticien</alt-title></titles><periodical><full-title>Rev Prat</full-title><abbr-1>La Revue du praticien</abbr-1></periodical><alt-periodical><full-title>Rev Prat</full-title><abbr-1>La Revue du praticien</abbr-1></alt-periodical><pages>155-66</pages><volume>54</volume><number>2</number><keywords><keyword>Antimetabolites, Antineoplastic/administration &amp; dosage/therapeutic use</keyword><keyword>Chemotherapy, Adjuvant</keyword><keyword>Colon/pathology</keyword><keyword>Colonoscopy</keyword><keyword>Colorectal Neoplasms/diagnosis/drug</keyword><keyword>therapy/mortality/pathology/radiotherapy/surgery/*therapy</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Endosonography</keyword><keyword>Fluorouracil/administration &amp; dosage/therapeutic use</keyword><keyword>Humans</keyword><keyword>Laparoscopy</keyword><keyword>Laparotomy</keyword><keyword>Leucovorin/administration &amp; dosage/therapeutic use</keyword><keyword>Liver Neoplasms/radiography/secondary</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Neoplasm Recurrence, Local</keyword><keyword>Neoplasm Staging</keyword><keyword>Preoperative Care</keyword><keyword>Prospective Studies</keyword><keyword>Radiotherapy, Adjuvant</keyword><keyword>Rectal Neoplasms/diagnosis/radiotherapy/surgery/therapy/ultrasonography</keyword><keyword>Rectum/pathology</keyword><keyword>Risk Factors</keyword><keyword>Tomography, Spiral Computed</keyword></keywords><dates><year>2004</year><pub-dates><date>Jan 31</date></pub-dates></dates><orig-pub>Prise en charge des tumeurs primitives colo-rectales.</orig-pub><isbn>0035-2640 (Print)&#xD;0035-2640 (Linking)</isbn><accession-num>15086058</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15086058 </url></related-urls></urls><language>fre</language></record></Cite></EndNote>[9] and chemotherapy is necessary. The modalities of surgery and adjuvant therapies are based on tumor extension and the possible existence of a revealing complication. Furthermore, it has been shown that overexpression of TLR4 in the tumor microenvironment can serve as a biomarker of disease progression as well as the target of therapy. In fact, induction of TLR4 signaling by LPS could improve the therapeutic results in patients with colorectal cancer  ADDIN EN.CITE <EndNote><Cite><Author>Hsu</Author><Year>2011</Year><RecNum>1</RecNum><record><rec-number>1</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hsu, R. Y.</author><author>Chan, C. H.</author><author>Spicer, J. D.</author><author>Rousseau, M. C.</author><author>Giannias, B.</author><author>Rousseau, S.</author><author>Ferri, L. E.</author></authors></contributors><auth-address>LD McLean Surgical Research Laboratories, Department of Surgery, McGill University, Montreal, Quebec, Canada.</auth-address><titles><title>LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis</title><secondary-title>Cancer Res</secondary-title><alt-title>Cancer research</alt-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><alt-periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></alt-periodical><pages>1989-98</pages><volume>71</volume><number>5</number><keywords><keyword>Animals</keyword><keyword>Antigens, Bacterial/*pharmacology</keyword><keyword>Antigens, CD29/metabolism</keyword><keyword>Blotting, Western</keyword><keyword>Cell Adhesion/drug effects</keyword><keyword>Cell Separation</keyword><keyword>Colorectal Neoplasms/metabolism/*pathology</keyword><keyword>Flow Cytometry</keyword><keyword>HT29 Cells</keyword><keyword>Humans</keyword><keyword>Lipopolysaccharides/*pharmacology</keyword><keyword>Liver Neoplasms/*metabolism/secondary</keyword><keyword>Lymphocyte Antigen 96/metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Nude</keyword><keyword>Microscopy, Fluorescence</keyword><keyword>Neoplasm Metastasis/pathology</keyword><keyword>Signal Transduction/drug effects/physiology</keyword><keyword>Toll-Like Receptor 4/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1538-7445 (Electronic)&#xD;0008-5472 (Linking)</isbn><accession-num>21363926</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21363926 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[10].
Therefore, the purpose of this study was to investigate the possible interaction of D299G and T399I polymorphisms of TLR4 with treatment of colorectal cancer in Tunisian population.
Material and methods
2.1 Subjects
A group of patients/control is collected from the Salah Azaiez hospital and Charles Nicolle hospital of Tunis (Tunisia). Patients concerns 100 unrelated sporadic CRC cases (45 women, 55 men, with age range 58 � 14) with no family cancer histories: they were classified on the bases of their histopathological profiles. Consent for the genetic study was obtained from volunteers. 
2.2 DNA extraction and genotyping of polymorphisms
Genomic DNA was extracted from peripheral blood leukocytes using conventional proteinase K digestion and phenol/chloroform extraction method. A NanoDrop (ND-1000) is used to quantify DNA. TLR4 variants D299G and T399I in patients and controls subjects were genotyped using specific primers for each polymorphism. PCR products were then analyzed using a primer extension method (SNaPshot)  ADDIN EN.CITE <EndNote><Cite><Author>Omrane</Author><Year>2014&#xD;</Year><RecNum>5</RecNum><record><rec-number>5</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Omrane, I.</author><author>Baroudi, O.</author><author>Bougatef, K.</author><author>Mezlini, A.</author><author>Abidi, A.</author><author>Medimegh, I.</author><author>Stambouli, N.</author><author>Ayari, H.</author><author>Kourda, N.</author><author>Uhrhammer, N.</author><author>Bignon, Y. J.</author><author>Benammar Elgaaied, A.</author><author>Marrakchi, R.</author></authors></contributors><auth-address>Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia. Electronic address: inesomrane@hotmail.fr.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Gastroenterology Service, Salah Azaiez hospital of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Anatomy and Pathology, Charles Nicolle Hospital of Tunis, Tunisia.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.</auth-address><titles><title>Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer</title><secondary-title>Immunol Lett</secondary-title><alt-title>Immunology letters</alt-title></titles><periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></periodical><alt-periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></alt-periodical><pages>189-94</pages><volume>158</volume><number>1-2</number><dates><year>2014</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1879-0542 (Electronic)&#xD;0165-2478 (Linking)</isbn><accession-num>24440568</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=24440568 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[6] .
2.3 Statistical analysis
The data were analyzed using SPSS software (version 11.5.). Significance of the association was determined by Pearson�s chi-squared test  , Fisher�s exact test and Anova test. A value of p � 0,05 was considered significant.
Results
In our study we evaluate the association between TLR4 D299G and T399I polymorphisms and treatments of CRC patients which were stratified according to surgery, neoadjuvant chemotherapy, adjuvant chemotherapy and preoperative radiotherapy.
 We found that the majority of patients were submitted to radical surgery. All patients with TLR4 T399I polymorphism were operated radically, similarly to those with D299G polymorphism except one patient who submitted to palliative surgery (table 1). In fact, we showed a significant association between D299G polymorphism of TLR4 and surgery (p=0,037; RR 6,49 (0,8-53,52)) unlike T399I polymorphism which shows no significant association with this type of treatment (p�0,05). In addition, we observed that all patients with T399I polymorphism and eleven from thirteen patients with D299G polymorphism had chemotherapy. Therefore, we showed a significant association between D299G and T399I polymorphisms and adjuvant chemotherapy treatment (p= 0,04; RR 4,26 (0,8-20,4) and p=0,042; RR1,11 (1,02-1,2)) respectively (table 1 and 2). 
Indeed, we showed that TLR4 polymorphisms could be a risk factor for surgery and neoadjuvant chemotherapy resulting in inefficiency of treatment.  
However, we did not find a significant association between D299G and T399I polymorphisms of TLR4 gene and neoadjuvant chemotherapy and preoperative radiotherapy (p�0,05) (table 1 and 2).
We next examined the additive effect these two variants of TLR4 gene on CRC risk. The combined frequency of genotypes harbouring D299G and T399I polymorphisms was significantly associated with adjuvant chemotherapy (p=0,035) (table 3). Then, we analyzed the distributions of common TLR4 haplotypes and their effects on CRC treatments.  Similarly, CG and TG haplotypes showed a significant association with CRC treatments, especially with radical surgery (p=0,038) and adjuvant chemotherapy (p=0,029) (table 4). Finally, we examined a possible association between TLR4 polymorphisms and overall survival (OS). However, we showed no significant association between TLR4 D299G and T399I polymorphisms and survival of patients with or without treatment (Data not show). 
Discussion 
	Colorectal cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. The most common treatment for colorectal cancer is surgery. Radiation therapy, which may be prescribed in rectal cancer, is more often associated with concomitant chemotherapy preoperatively. Chemotherapy can be prescribed as a preventive measure to prevent metastasis when the tumor grows in depth. Indeed, chemotherapy drugs are used in the treatment of several cancers because of their ability to block the uncontrolled growth of cancer cells. A recent study shows that the involvement of the immune system plays a crucial role in the effectiveness of these drugs  ADDIN EN.CITE <EndNote><Cite><Author>Ma</Author><Year>2013&#xD;</Year><RecNum>8</RecNum><record><rec-number>8</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ma, Y.</author><author>Adjemian, S.</author><author>Mattarollo, S. R.</author><author>Yamazaki, T.</author><author>Aymeric, L.</author><author>Yang, H.</author><author>Portela Catani, J. P.</author><author>Hannani, D.</author><author>Duret, H.</author><author>Steegh, K.</author><author>Martins, I.</author><author>Schlemmer, F.</author><author>Michaud, M.</author><author>Kepp, O.</author><author>Sukkurwala, A. Q.</author><author>Menger, L.</author><author>Vacchelli, E.</author><author>Droin, N.</author><author>Galluzzi, L.</author><author>Krzysiek, R.</author><author>Gordon, S.</author><author>Taylor, P. R.</author><author>Van Endert, P.</author><author>Solary, E.</author><author>Smyth, M. J.</author><author>Zitvogel, L.</author><author>Kroemer, G.</author></authors></contributors><auth-address>Institut National de la Sante et de la Recherche Medicale, Villejuif, France.</auth-address><titles><title>Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells</title><secondary-title>Immunity</secondary-title><alt-title>Immunity</alt-title></titles><periodical><full-title>Immunity</full-title><abbr-1>Immunity</abbr-1></periodical><alt-periodical><full-title>Immunity</full-title><abbr-1>Immunity</abbr-1></alt-periodical><pages>729-41</pages><volume>38</volume><number>4</number><keywords><keyword>Adoptive Transfer</keyword><keyword>Animals</keyword><keyword>Anthracyclines/*administration &amp; dosage/adverse effects</keyword><keyword>Antigen-Presenting Cells/*immunology</keyword><keyword>Antigens, CD11b/metabolism</keyword><keyword>Antigens, CD11c/metabolism</keyword><keyword>Antigens, Ly/metabolism</keyword><keyword>Antigens, Neoplasm/immunology</keyword><keyword>Antineoplastic Agents/*administration &amp; dosage/adverse effects</keyword><keyword>Apoptosis</keyword><keyword>Cell Differentiation/drug effects</keyword><keyword>Cell Line, Tumor</keyword><keyword>Cell Movement/drug effects</keyword><keyword>Dendritic Cells/*immunology</keyword><keyword>Granulocyte Precursor Cells/immunology</keyword><keyword>Immunity, Cellular</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Monocyte-Macrophage Precursor Cells/immunology</keyword><keyword>Neoplasms, Experimental/drug therapy/*immunology</keyword><keyword>Nucleotidases/metabolism</keyword><keyword>Receptors, Purinergic/metabolism</keyword></keywords><dates><year>2013&#xD;</year><pub-dates><date>Apr 18</date></pub-dates></dates><isbn>1097-4180 (Electronic)&#xD;1074-7613 (Linking)</isbn><accession-num>23562161</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=23562161 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[11].
The immune system is a biological system whose main role is to protect organism against external aggressions. These aggressions may be in the range of microbes such as viruses, bacteria, fungi, parasites or order of cancer cells. To adapt and improve treatment by immunotherapy in human cancers, it is necessary to understand the role of immunity genes polymorphisms such as Toll-like receptors TLR4. In fact, the TLR4 gene is located on chromosome 9 in the region (9q33.1). The existence of a mutation in this gene leads to changes in the responses against pathogens. There are two major polymorphisms: Asp299Gly (D299G; rs4986790) and Thr399IIe (T399I; rs4986791) that affect the extracellular domain of TLR4 protein thus leading to a decreased ability to detect bacterial components  ADDIN EN.CITE <EndNote><Cite><Author>Ferwerda</Author><Year>2008</Year><RecNum>3</RecNum><record><rec-number>3</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferwerda, B.</author><author>McCall, M. B.</author><author>Verheijen, K.</author><author>Kullberg, B. J.</author><author>van der Ven, A. J.</author><author>Van der Meer, J. W.</author><author>Netea, M. G.</author></authors></contributors><auth-address>Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. e.ferwerda@aig.umcn.nl</auth-address><titles><title>Functional consequences of toll-like receptor 4 polymorphisms</title><secondary-title>Mol Med</secondary-title><alt-title>Molecular medicine (Cambridge, Mass</alt-title></titles><periodical><full-title>Mol Med</full-title><abbr-1>Molecular medicine (Cambridge, Mass</abbr-1></periodical><alt-periodical><full-title>Mol Med</full-title><abbr-1>Molecular medicine (Cambridge, Mass</abbr-1></alt-periodical><pages>346-52</pages><volume>14</volume><number>5-6</number><keywords><keyword>Animals</keyword><keyword>Gene Frequency</keyword><keyword>Haplotypes</keyword><keyword>Humans</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Signal Transduction/genetics/physiology</keyword><keyword>Toll-Like Receptor 4/*genetics/*physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>1076-1551 (Print)&#xD;1076-1551 (Linking)</isbn><accession-num>18231573</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18231573 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[12]. TLR4 signaling is strongly involved in inflammatory processes  ADDIN EN.CITE <EndNote><Cite><Author>Franchimont</Author><Year>2004</Year><RecNum>10</RecNum><record><rec-number>10</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franchimont, D.</author><author>Vermeire, S.</author><author>El Housni, H.</author><author>Pierik, M.</author><author>Van Steen, K.</author><author>Gustot, T.</author><author>Quertinmont, E.</author><author>Abramowicz, M.</author><author>Van Gossum, A.</author><author>Deviere, J.</author><author>Rutgeerts, P.</author></authors></contributors><auth-address>Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. Denis.Franchimont@ulb.ac.be</auth-address><titles><title>Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn&apos;s disease and ulcerative colitis</title><secondary-title>Gut</secondary-title><alt-title>Gut</alt-title></titles><periodical><full-title>Gut</full-title><abbr-1>Gut</abbr-1></periodical><alt-periodical><full-title>Gut</full-title><abbr-1>Gut</abbr-1></alt-periodical><pages>987-92</pages><volume>53</volume><number>7</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Bacterial Infections/complications/*genetics</keyword><keyword>Carrier Proteins/genetics</keyword><keyword>Colitis, Ulcerative/*genetics/immunology/microbiology</keyword><keyword>Crohn Disease/*genetics/immunology/microbiology</keyword><keyword>Female</keyword><keyword>Gene Frequency</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>*Intracellular Signaling Peptides and Proteins</keyword><keyword>Male</keyword><keyword>Membrane Glycoproteins/*genetics</keyword><keyword>Nod2 Signaling Adaptor Protein</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Receptors, Cell Surface/*genetics</keyword><keyword>Toll-Like Receptor 4</keyword><keyword>Toll-Like Receptors</keyword></keywords><dates><year>2004</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0017-5749 (Print)&#xD;0017-5749 (Linking)</isbn><accession-num>15194649</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15194649 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Furrie</Author><Year>2005</Year><RecNum>24</RecNum><record><rec-number>24</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Furrie, E.</author><author>Macfarlane, S.</author><author>Thomson, G.</author><author>Macfarlane, G. T.</author></authors></contributors><auth-address>Ninewells Hospital Medical School, University of Dundee, Dundee, UK.</auth-address><titles><title>Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria</title><secondary-title>Immunology</secondary-title><alt-title>Immunology</alt-title></titles><periodical><full-title>Immunology</full-title><abbr-1>Immunology</abbr-1></periodical><alt-periodical><full-title>Immunology</full-title><abbr-1>Immunology</abbr-1></alt-periodical><pages>565-74</pages><volume>115</volume><number>4</number><keywords><keyword>Bacteroides fragilis/immunology</keyword><keyword>Bifidobacterium/immunology</keyword><keyword>Caco-2 Cells</keyword><keyword>Coculture Techniques/methods</keyword><keyword>Colon/*immunology/microbiology</keyword><keyword>Enterococcus faecalis/immunology</keyword><keyword>Epithelial Cells/immunology</keyword><keyword>Escherichia coli/immunology</keyword><keyword>Gene Expression Regulation, Bacterial/immunology</keyword><keyword>HT29 Cells</keyword><keyword>Humans</keyword><keyword>Immune Tolerance/immunology</keyword><keyword>Immunohistochemistry/methods</keyword><keyword>Interferon-beta/analysis</keyword><keyword>Intestinal Mucosa/immunology</keyword><keyword>Ligands</keyword><keyword>Membrane Glycoproteins/genetics/*immunology</keyword><keyword>Peptostreptococcus/immunology</keyword><keyword>RNA, Messenger/analysis</keyword><keyword>RNA, Viral/immunology</keyword><keyword>Receptors, Cell Surface/genetics/*immunology</keyword><keyword>Toll-Like Receptor 1</keyword><keyword>Toll-Like Receptor 2</keyword><keyword>Toll-Like Receptor 3</keyword><keyword>Toll-Like Receptors</keyword><keyword>Up-Regulation/immunology</keyword></keywords><dates><year>2005</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0019-2805 (Print)&#xD;0019-2805 (Linking)</isbn><accession-num>16011525</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16011525 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Oostenbrug</Author><Year>2005</Year><RecNum>40</RecNum><record><rec-number>40</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oostenbrug, L. E.</author><author>Drenth, J. P.</author><author>de Jong, D. J.</author><author>Nolte, I. M.</author><author>Oosterom, E.</author><author>van Dullemen, H. M.</author><author>van der Linde, K.</author><author>te Meerman, G. J.</author><author>van der Steege, G.</author><author>Kleibeuker, J. H.</author><author>Jansen, P. L.</author></authors></contributors><auth-address>Department of Gastroenterology and Hepatology, University of Groningen Medical Center, Groningen, The Netherlands. l.e.oostenbrug@inter.nl.net</auth-address><titles><title>Association between Toll-like receptor 4 and inflammatory bowel disease</title><secondary-title>Inflamm Bowel Dis</secondary-title><alt-title>Inflammatory bowel diseases</alt-title></titles><periodical><full-title>Inflamm Bowel Dis</full-title><abbr-1>Inflammatory bowel diseases</abbr-1></periodical><alt-periodical><full-title>Inflamm Bowel Dis</full-title><abbr-1>Inflammatory bowel diseases</abbr-1></alt-periodical><pages>567-75</pages><volume>11</volume><number>6</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age of Onset</keyword><keyword>Aged</keyword><keyword>Case-Control Studies</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genotype</keyword><keyword>Haplotypes</keyword><keyword>Humans</keyword><keyword>Inflammatory Bowel Diseases/*genetics/*physiopathology</keyword><keyword>Male</keyword><keyword>Membrane Glycoproteins/*genetics/*physiology</keyword><keyword>Microsatellite Repeats</keyword><keyword>Middle Aged</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Receptors, Cell Surface/*genetics/*physiology</keyword><keyword>Toll-Like Receptor 4</keyword><keyword>Toll-Like Receptors</keyword></keywords><dates><year>2005</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1078-0998 (Print)&#xD;1078-0998 (Linking)</isbn><accession-num>15905704</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15905704 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Brand</Author><Year>2005</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brand, S.</author><author>Staudinger, T.</author><author>Schnitzler, F.</author><author>Pfennig, S.</author><author>Hofbauer, K.</author><author>Dambacher, J.</author><author>Seiderer, J.</author><author>Tillack, C.</author><author>Konrad, A.</author><author>Crispin, A.</author><author>Goke, B.</author><author>Lohse, P.</author><author>Ochsenkuhn, T.</author></authors></contributors><auth-address>Department of Medicine II, University Hospital Munich-Grosshadern, University of Munich, Munich, Germany. stephan.brand@med.uni-muenchen.de</auth-address><titles><title>The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn&apos;s disease</title><secondary-title>Inflamm Bowel Dis</secondary-title><alt-title>Inflammatory bowel diseases</alt-title></titles><periodical><full-title>Inflamm Bowel Dis</full-title><abbr-1>Inflammatory bowel diseases</abbr-1></periodical><alt-periodical><full-title>Inflamm Bowel Dis</full-title><abbr-1>Inflammatory bowel diseases</abbr-1></alt-periodical><pages>645-52</pages><volume>11</volume><number>7</number><keywords><keyword>Adult</keyword><keyword>Case-Control Studies</keyword><keyword>Crohn Disease/*epidemiology/*genetics</keyword><keyword>Female</keyword><keyword>Genetic Predisposition to Disease/*epidemiology/*genetics</keyword><keyword>Germany/epidemiology</keyword><keyword>Heterozygote</keyword><keyword>Humans</keyword><keyword>Intracellular Signaling Peptides and Proteins/genetics</keyword><keyword>Linkage Disequilibrium</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Membrane Glycoproteins/*genetics</keyword><keyword>Middle Aged</keyword><keyword>Mutation</keyword><keyword>Nod2 Signaling Adaptor Protein</keyword><keyword>Phenotype</keyword><keyword>*Polymorphism, Single Nucleotide</keyword><keyword>Prevalence</keyword><keyword>Receptors, Cell Surface/*genetics</keyword><keyword>Statistics, Nonparametric</keyword><keyword>Toll-Like Receptor 4</keyword><keyword>Toll-Like Receptors</keyword></keywords><dates><year>2005</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1078-0998 (Print)&#xD;1078-0998 (Linking)</isbn><accession-num>15973118</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=15973118 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Ferwerda</Author><Year>2007</Year><RecNum>45</RecNum><record><rec-number>45</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ferwerda, B.</author><author>McCall, M. B.</author><author>Alonso, S.</author><author>Giamarellos-Bourboulis, E. J.</author><author>Mouktaroudi, M.</author><author>Izagirre, N.</author><author>Syafruddin, D.</author><author>Kibiki, G.</author><author>Cristea, T.</author><author>Hijmans, A.</author><author>Hamann, L.</author><author>Israel, S.</author><author>ElGhazali, G.</author><author>Troye-Blomberg, M.</author><author>Kumpf, O.</author><author>Maiga, B.</author><author>Dolo, A.</author><author>Doumbo, O.</author><author>Hermsen, C. C.</author><author>Stalenhoef, A. F.</author><author>van Crevel, R.</author><author>Brunner, H. G.</author><author>Oh, D. Y.</author><author>Schumann, R. R.</author><author>de la Rua, C.</author><author>Sauerwein, R.</author><author>Kullberg, B. J.</author><author>van der Ven, A. J.</author><author>van der Meer, J. W.</author><author>Netea, M. G.</author></authors></contributors><auth-address>Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.</auth-address><titles><title>TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></periodical><alt-periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></alt-periodical><pages>16645-50</pages><volume>104</volume><number>42</number><keywords><keyword>Adult</keyword><keyword>Alleles</keyword><keyword>Amino Acid Sequence</keyword><keyword>*Emigration and Immigration</keyword><keyword>*Evolution, Molecular</keyword><keyword>Female</keyword><keyword>Haplotypes</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/genetics</keyword><keyword>Infection/*genetics</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Phenotype</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Population/*genetics</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword></keywords><dates><year>2007</year><pub-dates><date>Oct 16</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>17925445</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17925445 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[13-17]. Previous studies have revealed that inflammation induced TLR are involved in carcinogenesis  ADDIN EN.CITE <EndNote><Cite><Author>El-Omar</Author><Year>2008</Year><RecNum>32</RecNum><record><rec-number>32</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>El-Omar, E. M.</author><author>Ng, M. T.</author><author>Hold, G. L.</author></authors></contributors><auth-address>Department of Medicine and Therapeutics, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen, UK. e.el-omar@abdn.ac.uk</auth-address><titles><title>Polymorphisms in Toll-like receptor genes and risk of cancer</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>244-52</pages><volume>27</volume><number>2</number><keywords><keyword>Carcinoma/etiology/genetics</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Helicobacter Infections/complications</keyword><keyword>Helicobacter pylori</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Neoplasms/etiology/*genetics</keyword><keyword>*Polymorphism, Single Nucleotide</keyword><keyword>Prostatic Neoplasms/etiology/genetics</keyword><keyword>Risk</keyword><keyword>Stomach Neoplasms/etiology/genetics</keyword><keyword>Toll-Like Receptor 2/genetics</keyword><keyword>Toll-Like Receptor 4/genetics</keyword><keyword>Toll-Like Receptor 5/genetics</keyword><keyword>Toll-Like Receptor 9/genetics</keyword><keyword>Toll-Like Receptors/*genetics</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>1476-5594 (Electronic)&#xD;0950-9232 (Linking)</isbn><accession-num>18176606</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18176606 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Fukata</Author><Year>2007</Year><RecNum>38</RecNum><record><rec-number>38</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fukata, M.</author><author>Chen, A.</author><author>Vamadevan, A. S.</author><author>Cohen, J.</author><author>Breglio, K.</author><author>Krishnareddy, S.</author><author>Hsu, D.</author><author>Xu, R.</author><author>Harpaz, N.</author><author>Dannenberg, A. J.</author><author>Subbaramaiah, K.</author><author>Cooper, H. S.</author><author>Itzkowitz, S. H.</author><author>Abreu, M. T.</author></authors></contributors><auth-address>Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, USA.</auth-address><titles><title>Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></periodical><alt-periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></alt-periodical><pages>1869-81</pages><volume>133</volume><number>6</number><keywords><keyword>Animals</keyword><keyword>Cell Line</keyword><keyword>Chronic Disease</keyword><keyword>Colitis/complications/*immunology</keyword><keyword>Colitis, Ulcerative/complications/immunology</keyword><keyword>Colorectal Neoplasms/*immunology</keyword><keyword>Cyclooxygenase 2/biosynthesis</keyword><keyword>Dinoprostone/biosynthesis</keyword><keyword>Disease Models, Animal</keyword><keyword>Genes, erbB-1/physiology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>Toll-Like Receptor 4/biosynthesis/*immunology</keyword><keyword>Up-Regulation</keyword></keywords><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1528-0012 (Electronic)&#xD;0016-5085 (Linking)</isbn><accession-num>18054559</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18054559 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Hold</Author><Year>2007</Year><RecNum>20</RecNum><record><rec-number>20</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hold, G. L.</author><author>Rabkin, C. S.</author><author>Chow, W. H.</author><author>Smith, M. G.</author><author>Gammon, M. D.</author><author>Risch, H. A.</author><author>Vaughan, T. L.</author><author>McColl, K. E.</author><author>Lissowska, J.</author><author>Zatonski, W.</author><author>Schoenberg, J. B.</author><author>Blot, W. J.</author><author>Mowat, N. A.</author><author>Fraumeni, J. F., Jr.</author><author>El-Omar, E. M.</author></authors></contributors><auth-address>Department of Medicine and Therapeutics, Aberdeen University, Aberdeen, Scotland.</auth-address><titles><title>A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></periodical><alt-periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></alt-periodical><pages>905-12</pages><volume>132</volume><number>3</number><keywords><keyword>Achlorhydria/genetics/microbiology</keyword><keyword>Carcinoma/*genetics/microbiology/pathology</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Europe</keyword><keyword>Female</keyword><keyword>Gastritis, Atrophic/genetics/microbiology</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>Gene Frequency</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genotype</keyword><keyword>Helicobacter Infections/complications/genetics/*microbiology</keyword><keyword>*Helicobacter pylori</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Odds Ratio</keyword><keyword>Phenotype</keyword><keyword>*Polymorphism, Genetic</keyword><keyword>Population Surveillance</keyword><keyword>Precancerous Conditions/*genetics/microbiology/pathology</keyword><keyword>Registries</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Stomach Neoplasms/*genetics/microbiology/pathology</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword><keyword>United States</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>17324405</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17324405 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[3, 18, 19] . Additionally, we lately showed that TLR4 polymorphisms (D299G and T399I) were associated with a severe form of colorectal cancer, particularly with advanced stage, lymph nodes and metastasis  ADDIN EN.CITE <EndNote><Cite><Author>Eyking</Author><Year>2011</Year><RecNum>6</RecNum><record><rec-number>6</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Eyking, A.</author><author>Ey, B.</author><author>Runzi, M.</author><author>Roig, A. I.</author><author>Reis, H.</author><author>Schmid, K. W.</author><author>Gerken, G.</author><author>Podolsky, D. K.</author><author>Cario, E.</author></authors></contributors><auth-address>Division of Gastroenterology &amp; Hepatology, University Hospital of Essen, Medical School, University of Duisburg-Essen, Essen, Germany.</auth-address><titles><title>Toll-like receptor 4 variant D299G induces features of neoplastic progression in Caco-2 intestinal cells and is associated with advanced human colon cancer</title><secondary-title>Gastroenterology</secondary-title><alt-title>Gastroenterology</alt-title></titles><periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></periodical><alt-periodical><full-title>Gastroenterology</full-title><abbr-1>Gastroenterology</abbr-1></alt-periodical><pages>2154-65</pages><volume>141</volume><number>6</number><keywords><keyword>Adenocarcinoma/genetics/metabolism/*pathology</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Animals</keyword><keyword>Caco-2 Cells</keyword><keyword>Colonic Neoplasms/genetics/metabolism/*pathology</keyword><keyword>*Disease Progression</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Epithelial-Mesenchymal Transition</keyword><keyword>Female</keyword><keyword>Gene Expression Profiling</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Immunoblotting</keyword><keyword>Inflammation/immunology</keyword><keyword>Intestinal Mucosa/*drug effects</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Microscopy, Fluorescence</keyword><keyword>Middle Aged</keyword><keyword>Oligonucleotide Array Sequence Analysis</keyword><keyword>RNA, Messenger/genetics</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction</keyword><keyword>STAT3 Transcription Factor/metabolism</keyword><keyword>Toll-Like Receptor 4/*physiology</keyword><keyword>Wnt Signaling Pathway</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1528-0012 (Electronic)&#xD;0016-5085 (Linking)</isbn><accession-num>21920464</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21920464 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Slattery</Author><Year>2012</Year><RecNum>8</RecNum><record><rec-number>8</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Slattery, M. L.</author><author>Herrick, J. S.</author><author>Bondurant, K. L.</author><author>Wolff, R. K.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA. marty.slattery@hsc.utah.edu</auth-address><titles><title>Toll-like receptor genes and their association with colon and rectal cancer development and prognosis</title><secondary-title>Int J Cancer</secondary-title><alt-title>International journal of cancer</alt-title></titles><periodical><full-title>Int J Cancer</full-title><abbr-1>International journal of cancer</abbr-1></periodical><alt-periodical><full-title>Int J Cancer</full-title><abbr-1>International journal of cancer</abbr-1></alt-periodical><pages>2974-80</pages><volume>130</volume><number>12</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Case-Control Studies</keyword><keyword>Colonic Neoplasms/epidemiology/*genetics</keyword><keyword>Female</keyword><keyword>Genetic Association Studies</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genetic Variation</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Interviews as Topic</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Polymorphism, Single Nucleotide</keyword><keyword>Prognosis</keyword><keyword>Rectal Neoplasms/epidemiology/*genetics</keyword><keyword>Risk Factors</keyword><keyword>Toll-Like Receptor 2/*genetics</keyword><keyword>Toll-Like Receptor 3/*genetics</keyword><keyword>Toll-Like Receptor 4/*genetics</keyword><keyword>Tumor Markers, Biological</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>1097-0215 (Electronic)&#xD;0020-7136 (Linking)</isbn><accession-num>21792899</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21792899 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Omrane</Author><Year>2014&#xD;</Year><RecNum>5</RecNum><record><rec-number>5</rec-number><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Omrane, I.</author><author>Baroudi, O.</author><author>Bougatef, K.</author><author>Mezlini, A.</author><author>Abidi, A.</author><author>Medimegh, I.</author><author>Stambouli, N.</author><author>Ayari, H.</author><author>Kourda, N.</author><author>Uhrhammer, N.</author><author>Bignon, Y. J.</author><author>Benammar Elgaaied, A.</author><author>Marrakchi, R.</author></authors></contributors><auth-address>Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia. Electronic address: inesomrane@hotmail.fr.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Gastroenterology Service, Salah Azaiez hospital of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Anatomy and Pathology, Charles Nicolle Hospital of Tunis, Tunisia.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.&#xD;Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.</auth-address><titles><title>Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer</title><secondary-title>Immunol Lett</secondary-title><alt-title>Immunology letters</alt-title></titles><periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></periodical><alt-periodical><full-title>Immunol Lett</full-title><abbr-1>Immunology letters</abbr-1></alt-periodical><pages>189-94</pages><volume>158</volume><number>1-2</number><dates><year>2014</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1879-0542 (Electronic)&#xD;0165-2478 (Linking)</isbn><accession-num>24440568</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=24440568 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Simiantonaki</Author><Year>2007</Year><RecNum>27</RecNum><record><rec-number>27</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simiantonaki, N.</author><author>Kurzik-Dumke, U.</author><author>Karyofylli, G.</author><author>Jayasinghe, C.</author><author>Michel-Schmidt, R.</author><author>Kirkpatrick, C. J.</author></authors></contributors><auth-address>Institute of Pathology, Johannes Gutenberg University, Mainz, Germany. simiantonaki@klinikum-lev.de</auth-address><titles><title>Reduced expression of TLR4 is associated with the metastatic status of human colorectal cancer</title><secondary-title>Int J Mol Med</secondary-title><alt-title>International journal of molecular medicine</alt-title></titles><periodical><full-title>Int J Mol Med</full-title><abbr-1>International journal of molecular medicine</abbr-1></periodical><alt-periodical><full-title>Int J Mol Med</full-title><abbr-1>International journal of molecular medicine</abbr-1></alt-periodical><pages>21-9</pages><volume>20</volume><number>1</number><keywords><keyword>Antigens, CD14/metabolism</keyword><keyword>Caco-2 Cells</keyword><keyword>Carcinoma/*pathology/surgery</keyword><keyword>Cell Line, Tumor</keyword><keyword>Colorectal Neoplasms/*pathology/surgery</keyword><keyword>Fluorescent Antibody Technique, Indirect</keyword><keyword>*Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Lipopolysaccharides/*metabolism/pharmacology</keyword><keyword>Lymphatic Metastasis/pathology</keyword><keyword>Neoplasm Metastasis/pathology</keyword><keyword>Neoplasm Staging</keyword><keyword>Retrospective Studies</keyword><keyword>Toll-Like Receptor 4/genetics/*metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1107-3756 (Print)&#xD;1107-3756 (Linking)</isbn><accession-num>17549384</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17549384 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[6-8, 20].
	Here, we demonstrated the association between TLR4 polymorphisms and colorectal cancer treatments. We showed that TLR4 D299G and T399I variants are associated with a poor prognosis for treatment according to surgery and adjuvant chemotherapy (p= 0,04; RR 4,26 (0,8-20,4) and p=0,042) respectively. Moreover, by studying haplotypes of TLR4 variants, we found that haplotypes with mutated alleles are also associated with radical surgery and chemotherapy ((p=0,038 and p= 0,029) respectively). However, the combined genotypes of these two variants of TLR4 are significantly associated only with the adjuvant chemotherapy (p=0,035). This poor response to treatment in patients with the mutated alleles of D299G and T399I could be explained by the disruption of the TLR4 signaling pathway. Indeed, Davoodi et al, showed that 5-Fluorouracil (5-FU) increased TLR4 expression to induced apoptosis in colorectal cancer cells in the presence and absence of LPS. They also found that wild type TLR4 expressing cells are more sensitive to 5-FU treatment compared to cells expressing TLR4 variants (D299G and T399I). On the other hand, Lionel Apetoh showed that TLR4 polymorphism predicts early relapse after chemotherapy in breast cancer patients  ADDIN EN.CITE <EndNote><Cite><Author>Apetoh</Author><Year>2007</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Apetoh, L.</author><author>Ghiringhelli, F.</author><author>Tesniere, A.</author><author>Criollo, A.</author><author>Ortiz, C.</author><author>Lidereau, R.</author><author>Mariette, C.</author><author>Chaput, N.</author><author>Mira, J. P.</author><author>Delaloge, S.</author><author>Andre, F.</author><author>Tursz, T.</author><author>Kroemer, G.</author><author>Zitvogel, L.</author></authors></contributors><auth-address>Institut Gustave Roussy (IGR), Villejuif, France.</auth-address><titles><title>The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy</title><secondary-title>Immunol Rev</secondary-title><alt-title>Immunological reviews</alt-title></titles><periodical><full-title>Immunol Rev</full-title><abbr-1>Immunological reviews</abbr-1></periodical><alt-periodical><full-title>Immunol Rev</full-title><abbr-1>Immunological reviews</abbr-1></alt-periodical><pages>47-59</pages><volume>220</volume><keywords><keyword>Animals</keyword><keyword>Anthracyclines/therapeutic use</keyword><keyword>Antineoplastic Agents/therapeutic use</keyword><keyword>*Apoptosis</keyword><keyword>Dendritic Cells/immunology</keyword><keyword>HMGB1 Protein/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Neoplasms/*drug therapy/*immunology/radiotherapy</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Toll-Like Receptor 4/genetics/*metabolism</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0105-2896 (Print)&#xD;0105-2896 (Linking)</isbn><accession-num>17979839</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17979839 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Apetoh</Author><Year>2007</Year><RecNum>10</RecNum><record><rec-number>10</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Apetoh, L.</author><author>Ghiringhelli, F.</author><author>Tesniere, A.</author><author>Obeid, M.</author><author>Ortiz, C.</author><author>Criollo, A.</author><author>Mignot, G.</author><author>Maiuri, M. C.</author><author>Ullrich, E.</author><author>Saulnier, P.</author><author>Yang, H.</author><author>Amigorena, S.</author><author>Ryffel, B.</author><author>Barrat, F. J.</author><author>Saftig, P.</author><author>Levi, F.</author><author>Lidereau, R.</author><author>Nogues, C.</author><author>Mira, J. P.</author><author>Chompret, A.</author><author>Joulin, V.</author><author>Clavel-Chapelon, F.</author><author>Bourhis, J.</author><author>Andre, F.</author><author>Delaloge, S.</author><author>Tursz, T.</author><author>Kroemer, G.</author><author>Zitvogel, L.</author></authors></contributors><auth-address>Institut Gustave Roussy (IGR), 39 rue Camille Desmoulins, F-94805 Villejuif, France.</auth-address><titles><title>Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy</title><secondary-title>Nat Med</secondary-title><alt-title>Nature medicine</alt-title></titles><periodical><full-title>Nat Med</full-title><abbr-1>Nature medicine</abbr-1></periodical><alt-periodical><full-title>Nat Med</full-title><abbr-1>Nature medicine</abbr-1></alt-periodical><pages>1050-9</pages><volume>13</volume><number>9</number><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents/*therapeutic use</keyword><keyword>Bone Neoplasms/drug therapy</keyword><keyword>Cell Line, Tumor</keyword><keyword>Colonic Neoplasms/drug therapy/radiotherapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Inbred BALB C</keyword><keyword>Neoplasms/*drug therapy/*radiotherapy</keyword><keyword>Organoplatinum Compounds/therapeutic use</keyword><keyword>Osteosarcoma/drug therapy</keyword><keyword>Pyridines/therapeutic use</keyword><keyword>Toll-Like Receptor 4/*immunology</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1078-8956 (Print)&#xD;1078-8956 (Linking)</isbn><accession-num>17704786</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17704786 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[21, 22]. Bergmann et al. demonstrated that head and neck cancer patients with TLR4 wild-type genotype showed significantly longer disease-free survival  ADDIN EN.CITE <EndNote><Cite><Author>Bergmann</Author><Year>2011&#xD;</Year><RecNum>1</RecNum><record><rec-number>1</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bergmann, C.</author><author>Bachmann, H. S.</author><author>Bankfalvi, A.</author><author>Lotfi, R.</author><author>Putter, C.</author><author>Wild, C. A.</author><author>Schuler, P. J.</author><author>Greve, J.</author><author>Hoffmann, T. K.</author><author>Lang, S.</author><author>Scherag, A.</author><author>Lehnerdt, G. F.</author></authors></contributors><auth-address>Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstrasse 55, 45127 Essen, Germany. christoph.bergmann@uk-essen.de</auth-address><titles><title>Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas</title><secondary-title>J Transl Med</secondary-title><alt-title>Journal of translational medicine</alt-title></titles><periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></periodical><alt-periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></alt-periodical><pages>139</pages><volume>9</volume><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution/*genetics</keyword><keyword>Carcinoma, Squamous Cell/*genetics/pathology</keyword><keyword>Chemotherapy, Adjuvant</keyword><keyword>Disease Progression</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Head and Neck Neoplasms/*genetics/pathology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multivariate Analysis</keyword><keyword>Polymorphism, Single Nucleotide/*genetics</keyword><keyword>Proportional Hazards Models</keyword><keyword>Recurrence</keyword><keyword>Survival Analysis</keyword><keyword>Toll-Like Receptor 4/*genetics/metabolism</keyword></keywords><dates><year>2011&#xD;</year></dates><isbn>1479-5876 (Electronic)&#xD;1479-5876 (Linking)</isbn><accession-num>21854645</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21854645 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[23]. 
Microbial products have been utilized as adjuvants to stimulate TLR signaling and activating immune responses to enhance tumor immunotherapy. Okamoto et al also showed an antitumor activity of TLR4 /IFN-� signaling using streptococcal agent OK-432  ADDIN EN.CITE <EndNote><Cite><Author>Okamoto</Author><Year>2006</Year><RecNum>2</RecNum><record><rec-number>2</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Okamoto, M.</author><author>Oshikawa, T.</author><author>Tano, T.</author><author>Ahmed, S. U.</author><author>Kan, S.</author><author>Sasai, A.</author><author>Akashi, S.</author><author>Miyake, K.</author><author>Moriya, Y.</author><author>Ryoma, Y.</author><author>Saito, M.</author><author>Sato, M.</author></authors></contributors><auth-address>Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Tokushima, Japan. mokamoto@dent.tokushima-u.ac.jp</auth-address><titles><title>Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and Toll-like receptor 4 signaling</title><secondary-title>J Immunother</secondary-title></titles><periodical><full-title>J Immunother</full-title></periodical><pages>78-86</pages><volume>29</volume><number>1</number><keywords><keyword>*Adjuvants, Immunologic</keyword><keyword>Animals</keyword><keyword>Dendritic Cells/immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Macrophages, Peritoneal/immunology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred BALB C</keyword><keyword>Neoplasms/*immunology</keyword><keyword>Phagocytosis/*immunology</keyword><keyword>Picibanil/*immunology/metabolism</keyword><keyword>Signal Transduction/*immunology</keyword><keyword>Toll-Like Receptor 4/*immunology</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1524-9557 (Print)&#xD;1524-9557 (Linking)</isbn><accession-num>16365603</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16365603 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[24]. However, TLR4, the receptor for lipopolysaccharide, activate both MyD88-dependent and TRIF dependent or MyD88-independent pathways. MyD88 is an adaptor protein for TLR4 signaling implicated on NF-kB, MAPK and PI3K pathways activation driving tumor survival and paclitaxel chemoresistance in epithelial ovarian carcinoma cells  ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>2008</Year><RecNum>6</RecNum><record><rec-number>6</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, R.</author><author>Alvero, A. B.</author><author>Silasi, D. A.</author><author>Steffensen, K. D.</author><author>Mor, G.</author></authors></contributors><auth-address>Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.</auth-address><titles><title>Cancers take their Toll--the function and regulation of Toll-like receptors in cancer cells</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>225-33</pages><volume>27</volume><number>2</number><keywords><keyword>Disease Progression</keyword><keyword>Drug Resistance, Neoplasm/genetics</keyword><keyword>Epigenesis, Genetic/physiology</keyword><keyword>Female</keyword><keyword>*Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>Inflammation/complications</keyword><keyword>MicroRNAs/therapeutic use</keyword><keyword>Models, Biological</keyword><keyword>Myeloid Differentiation Factor 88/physiology</keyword><keyword>NF-kappa B/physiology</keyword><keyword>Neoplasms/etiology/*genetics/pathology/therapy</keyword><keyword>Neutrophil Infiltration/immunology</keyword><keyword>Ovarian Neoplasms/genetics/immunology</keyword><keyword>Signal Transduction/genetics</keyword><keyword>Toll-Like Receptor 4/physiology</keyword><keyword>Toll-Like Receptors/*genetics/metabolism/*physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>1476-5594 (Electronic)&#xD;0950-9232 (Linking)</isbn><accession-num>18176604</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18176604 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Kim</Author><Year>2012&#xD;</Year><RecNum>5</RecNum><record><rec-number>5</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, K. H.</author><author>Jo, M. S.</author><author>Suh, D. S.</author><author>Yoon, M. S.</author><author>Shin, D. H.</author><author>Lee, J. H.</author><author>Choi, K. U.</author></authors></contributors><auth-address>Department of Pathology, Pusan National University Yangsan Hospital, Beomeo-ri, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, 626-770, Republic of Korea.</auth-address><titles><title>Expression and significance of the TLR4/MyD88 signaling pathway in ovarian epithelial cancers</title><secondary-title>World J Surg Oncol</secondary-title><alt-title>World journal of surgical oncology</alt-title></titles><periodical><full-title>World J Surg Oncol</full-title><abbr-1>World journal of surgical oncology</abbr-1></periodical><alt-periodical><full-title>World J Surg Oncol</full-title><abbr-1>World journal of surgical oncology</abbr-1></alt-periodical><pages>193</pages><volume>10</volume><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Case-Control Studies</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Middle Aged</keyword><keyword>Multivariate Analysis</keyword><keyword>Myeloid Differentiation Factor 88/*metabolism</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>Neoplasm Grading</keyword><keyword>Neoplasm Recurrence, Local</keyword><keyword>Neoplasm Staging</keyword><keyword>Neoplasms, Glandular and Epithelial/*metabolism/mortality/pathology</keyword><keyword>Ovarian Neoplasms/*metabolism/mortality/pathology</keyword><keyword>Single-Blind Method</keyword><keyword>Survival Analysis</keyword><keyword>Toll-Like Receptor 4/*metabolism</keyword><keyword>Tumor Burden</keyword><keyword>Tumor Markers, Biological/*metabolism</keyword><keyword>Young Adult</keyword></keywords><dates><year>2012&#xD;</year></dates><isbn>1477-7819 (Electronic)&#xD;1477-7819 (Linking)</isbn><accession-num>22985132</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=22985132 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Szajnik</Author><Year>2009</Year><RecNum>3</RecNum><record><rec-number>3</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Szajnik, M.</author><author>Szczepanski, M. J.</author><author>Czystowska, M.</author><author>Elishaev, E.</author><author>Mandapathil, M.</author><author>Nowak-Markwitz, E.</author><author>Spaczynski, M.</author><author>Whiteside, T. L.</author></authors></contributors><auth-address>University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.</auth-address><titles><title>TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>4353-63</pages><volume>28</volume><number>49</number><keywords><keyword>Carcinoma/genetics/metabolism/*pathology</keyword><keyword>Cell Proliferation/drug effects</keyword><keyword>Cell Survival/drug effects</keyword><keyword>Cytokines/metabolism</keyword><keyword>Drug Resistance, Neoplasm/*drug effects/genetics</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation, Neoplastic/drug effects</keyword><keyword>Humans</keyword><keyword>Lipopolysaccharides/*pharmacology</keyword><keyword>Myeloid Differentiation Factor 88/genetics/physiology</keyword><keyword>NF-kappa B/metabolism/physiology</keyword><keyword>Ovarian Neoplasms/genetics/metabolism/*pathology</keyword><keyword>Paclitaxel/*pharmacology</keyword><keyword>Signal Transduction/drug effects/genetics</keyword><keyword>Toll-Like Receptor 4/genetics/metabolism/*physiology</keyword><keyword>Tumor Cells, Cultured</keyword><keyword>Tumor Escape/drug effects/genetics</keyword><keyword>Up-Regulation/drug effects</keyword></keywords><dates><year>2009</year><pub-dates><date>Dec 10</date></pub-dates></dates><isbn>1476-5594 (Electronic)&#xD;0950-9232 (Linking)</isbn><accession-num>19826413</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=19826413 </url></related-urls></urls><language>eng</language></record></Cite><Cite><Author>Zhu</Author><Year>2012&#xD;</Year><RecNum>4</RecNum><record><rec-number>4</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhu, Y.</author><author>Huang, J. M.</author><author>Zhang, G. N.</author><author>Zha, X.</author><author>Deng, B. F.</author></authors></contributors><auth-address>Department of Gynecologic Oncology, Sichuan Cancer Hospital, Sichuan, People&apos;s Republic of China.</auth-address><titles><title>Prognostic significance of MyD88 expression by human epithelial ovarian carcinoma cells</title><secondary-title>J Transl Med</secondary-title><alt-title>Journal of translational medicine</alt-title></titles><periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></periodical><alt-periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></alt-periodical><pages>77</pages><volume>10</volume><keywords><keyword>Blotting, Western</keyword><keyword>Cell Line, Tumor</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Middle Aged</keyword><keyword>Myeloid Differentiation Factor 88/*metabolism</keyword><keyword>Neoplasms, Glandular and Epithelial/*metabolism/pathology</keyword><keyword>Ovarian Neoplasms/*metabolism/pathology</keyword><keyword>Retrospective Studies</keyword><keyword>Survival Rate</keyword><keyword>Toll-Like Receptor 4/metabolism</keyword></keywords><dates><year>2012&#xD;</year></dates><isbn>1479-5876 (Electronic)&#xD;1479-5876 (Linking)</isbn><accession-num>22533866</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=22533866 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[25-28]. Sandeep Rajput et al showed that the inhibition of TLR4 may enhance the response to chemotherapy against breast cancer based on Paclitaxel, a known TLR4 ligand. In fact, they showed that the paclitaxel kill not only tumor cells but also improves their survival by activating TLR4/MyD88-dependent pathway  ADDIN EN.CITE <EndNote><Cite><Author>Rajput</Author><Year>2013</Year><RecNum>7</RecNum><record><rec-number>7</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rajput, S.</author><author>Volk-Draper, L. D.</author><author>Ran, S.</author></authors></contributors><auth-address>Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.</auth-address><titles><title>TLR4 is a novel determinant of the response to paclitaxel in breast cancer</title><secondary-title>Mol Cancer Ther</secondary-title><alt-title>Molecular cancer therapeutics</alt-title></titles><periodical><full-title>Mol Cancer Ther</full-title><abbr-1>Molecular cancer therapeutics</abbr-1></periodical><alt-periodical><full-title>Mol Cancer Ther</full-title><abbr-1>Molecular cancer therapeutics</abbr-1></alt-periodical><pages>1676-87</pages><volume>12</volume><number>8</number><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents, Phytogenic/*pharmacology</keyword><keyword>Apoptosis Regulatory Proteins/genetics/metabolism</keyword><keyword>Autocrine Communication</keyword><keyword>Breast Neoplasms/drug therapy/*genetics/metabolism</keyword><keyword>Cell Line, Tumor</keyword><keyword>Cell Survival/drug effects/genetics</keyword><keyword>Disease Models, Animal</keyword><keyword>Drug Resistance, Neoplasm/*genetics</keyword><keyword>Female</keyword><keyword>*Gene Expression</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mitogen-Activated Protein Kinase 1/metabolism</keyword><keyword>Mitogen-Activated Protein Kinase 3/metabolism</keyword><keyword>Paclitaxel/*pharmacology</keyword><keyword>Phosphorylation</keyword><keyword>Proto-Oncogene Proteins c-akt/metabolism</keyword><keyword>Receptors, Cytokine/metabolism</keyword><keyword>Toll-Like Receptor 4/*genetics/metabolism</keyword><keyword>Transcriptional Activation/drug effects</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1538-8514 (Electronic)&#xD;1535-7163 (Linking)</isbn><accession-num>23720768</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=23720768 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[29]. On the other hand, Jian-Ming Huang et al, demonstrated that atractylenolide-I, TLR4-antagonizing agent, sensitizes epithelial ovarian carcinoma cells to paclitaxel by blocking TLR4/MyD88-dependent pathway  ADDIN EN.CITE <EndNote><Cite><Author>Huang</Author><Year>2014</Year><RecNum>8</RecNum><record><rec-number>8</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Huang, J. M.</author><author>Zhang, G. N.</author><author>Shi, Y.</author><author>Zha, X.</author><author>Zhu, Y.</author><author>Wang, M. M.</author><author>Lin, Q.</author><author>Wang, W.</author><author>Lu, H. Y.</author><author>Ma, S. Q.</author><author>Cheng, J.</author><author>Deng, B. F.</author></authors></contributors><auth-address>1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Biochemistry &amp; Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.&#xD;1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China [2] Graduate School, Guangxi Medical University, Nanning 530021, Guangxi, P. R. China.&#xD;Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China.&#xD;1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Biochemistry &amp; Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.&#xD;1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Ultrasound, Sichuan Cancer Hospital, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People&apos;s Road, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Biochemistry &amp; Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Biochemistry &amp; Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.&#xD;Department of Biochemistry &amp; Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.</auth-address><titles><title>Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway</title><secondary-title>Sci Rep</secondary-title><alt-title>Scientific reports</alt-title></titles><periodical><full-title>Sci Rep</full-title><abbr-1>Scientific reports</abbr-1></periodical><alt-periodical><full-title>Sci Rep</full-title><abbr-1>Scientific reports</abbr-1></alt-periodical><pages>3840</pages><volume>4</volume><dates><year>2014</year></dates><isbn>2045-2322 (Electronic)&#xD;2045-2322 (Linking)</isbn><accession-num>24452475</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=24452475 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[30].
Finally, activation of TLR4 signaling is needed for host protection against pathogens. TLR ligands can be employed as immunological adjuvants in tumors effective immunotherapy.  Nevertheless, TLR activation may be considered as a two-edged sword. In fact, TLR4 plays an ambivalent role with both antitumor and pro-tumor effect. 
We observed no significant association between TLR4 D299G and T399I polymorphisms and survival of patients with or without treatment. Christoph Bergmann et al showed a significant association between TLR4 D299G polymorphisms and recurrence of disease as well as overall survival in patients with head and neck squamous cell carcinomas. They also showed a significant association between longer DFS and patients with D299G wild-type genotype and under adjuvant systemic therapy. However, no evidence for significant survival differences between TLR4 genotypes in patients without adjuvant systemic therapy  ADDIN EN.CITE <EndNote><Cite><Author>Bergmann</Author><Year>2011</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bergmann, C.</author><author>Bachmann, H. S.</author><author>Bankfalvi, A.</author><author>Lotfi, R.</author><author>Putter, C.</author><author>Wild, C. A.</author><author>Schuler, P. J.</author><author>Greve, J.</author><author>Hoffmann, T. K.</author><author>Lang, S.</author><author>Scherag, A.</author><author>Lehnerdt, G. F.</author></authors></contributors><auth-address>Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstrasse 55, 45127 Essen, Germany. christoph.bergmann@uk-essen.de</auth-address><titles><title>Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas</title><secondary-title>J Transl Med</secondary-title><alt-title>Journal of translational medicine</alt-title></titles><periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></periodical><alt-periodical><full-title>J Transl Med</full-title><abbr-1>Journal of translational medicine</abbr-1></alt-periodical><pages>139</pages><volume>9</volume><keywords><keyword>Alleles</keyword><keyword>Amino Acid Substitution/*genetics</keyword><keyword>Carcinoma, Squamous Cell/*genetics/pathology</keyword><keyword>Chemotherapy, Adjuvant</keyword><keyword>Disease Progression</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>*Genetic Predisposition to Disease</keyword><keyword>Head and Neck Neoplasms/*genetics/pathology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multivariate Analysis</keyword><keyword>Polymorphism, Single Nucleotide/*genetics</keyword><keyword>Proportional Hazards Models</keyword><keyword>Recurrence</keyword><keyword>Survival Analysis</keyword><keyword>Toll-Like Receptor 4/*genetics/metabolism</keyword></keywords><dates><year>2011</year></dates><isbn>1479-5876 (Electronic)&#xD;1479-5876 (Linking)</isbn><accession-num>21854645</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21854645 </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[31].
In conclusion, we showed a significant association between TL4 polymorphisms (D299G and T399I) and colorectal cancer treatment, particularly with surgery and chemotherapy. We suggest that mutant alleles of TLR4 polymorphisms might be predictive of the choice of nature therapy. Further investigations and an advanced exploration of the relationship between TLR4 and tumor micro environment are now needed to clarify the mechanisms of tumor progression and metastasis and to develop more effective therapeutic approaches and new therapeutic targets in cancer therapy. 
Abbreviations: 
TLR4: Toll like receptor 4; LPS: Lipopolysaccharide; CRC: Colorectal cancer; CD: Crohn�s disease; UC: ulcerative colitis MyD88: Myeloid differentiation factor 88; 5FU: 5-Fluorouracil; NF-�B: Nuclear factor �B; TRIF: TIR domain-containing adaptor protein inducing interferon-�; PI3K: phosphatidylinositide 3-kinases; MAPK : Mitogen-activated protein kinases�
Acknowledgments
We would like to thank all the members of  Laboratoire de G�n�tique, Immunologie et Pathologie Humaine� for their support and cooperation.
Disclosure statement
No competing financial interests exist.












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Table 1.Association between TLR4 T399I polymorphism and CRC treatments
T399I TLR4�GenotypesCCCTp valueSurgerypalliative and non-palliative surgery n=32            3200,092radical surgery n= 68            626Neoadjuvant chemotherapyNo n=7571      40,46Yes n=2523      2Adjuvant chemotherapyNo n=4040     00,042
RR 1,11 
(1,02-1,2)Yes n=6054     6Preoperative radiotherapy (dose in Gy) No   n= 7572   30,16Yes n= 2522     3

















	






Table 2.Association between TLR4 D299G polymorphism and CRC treatments
D299G TLR4AAAGp valueSurgerypalliative and non-palliative surgery n=323210,037
RR 6,49 (0,8-53,52)radical surgery n= 68"%7ABCDGOPR^_a���֭��taPa@/@!h�R�CJH*OJQJaJmH	sH	h�R�CJOJQJaJmH	sH	!h�U�CJH*OJQJaJmH	sH	$hbCh�U�CJOJQJaJmH	sH	h�U�CJOJQJaJmH	sH	+h_3�h�+5�CJ$OJQJ^JaJ$mH	sH	%h93�5�CJ$OJQJ^JaJ$mH	sH	%h�u�5�CJ$OJQJ^JaJ$mH	sH	+h�u�h�	�5�CJ$OJQJ^JaJ$mH	sH	+h�u�h�u�5�CJ$OJQJ^JaJ$mH	sH	%h�	�5�CJ$OJQJ^JaJ$mH	sH	BCD�M	�	�	�	�	�	�	�


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Table 3. Association between combined genotype of D299G and T399I polymorphisms and CRC treatments

Combined
genotypes (D299G/T399I)Surgeryp-value�palliative and non-palliative surgeryradical surgery�CCAA31570,056CCAG15CTGG06�Combined genotype (D299G/T399I)Neoadjuvant chemotherapyp-value�NOYES�CCAA66220,7CCAG51CTGG42�Combined genotype (D299G/T399I)Adjuvant chemotherapyp-value�NOYES�CCAA38500,035CCAG24CTGG06�Combined genotype (D299G/T399I)Preoperative radiotherapy (dose in Gy) p-value�NOYES�CCAA67210,31CCAG51CTGG33�









Table 4. Association between TLR4 D299G and T399I haplotypes and CRC treatments


HaplotypesSurgeryp-value�palliative and non-palliative surgeryradical surgery�CA31560,038CG16TG06�Haplotypesneoadjuvant chemotherapyp-value�NOYES�CA65220,7CG61TG42�HaplotypesAdjuvant chemotherapyp-value�NOYES�CA38490,029CG25TG06�HaplotypesPreoperative radiotherapy (dose in Gy) p-value�NOYES�CA66210,3CG61TG33�



























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