Expression and Polymorphism of Toll-Like Receptor 4 and Effect on NF-κB Mediated Inflammation in Colon Cancer Patients

Our aim was to evaluate the association between the expression and the polymorphism of TLR4/NF-κB pathways and colon cancer. TLR4 (rs4986790, rs10759932, rs10759931 and rs2770150) were genotyped in blood samples from Colorectal patients and healthy controls. TLR4 and cytokines inflammatory expression were evaluated by real time PCR on 40 matching normal and colon tissues and the protein level by Immunohistochemistry. The high level of TLR4 expression in colon cancer tissues is mainly due to infections by bacteria in the human colon and leads to induction of an acute secretion of inflammatory cytokines mediated by NF-κB. Also, we report here a clear evidence for an association between TLR4 rs10759931 polymorphism (OR = 0.086, CI: 0.04–0.18, P = <0.00001). This polymorphism affects the entire population without being specific to either gender or to any age group. In contrast, the rs2770150 is associated with colon cancer in women aged over 50 years and is closely linked with the decreased levels of female sex hormones during the post-menopausal period (OR = 0.188, CI: 0.074–0.48, P = <0.00084). rs10759932 and rs4986790 appear to have any association with colon cancer. Our data suggest that TLR4 SNPs could possibly serve as biomarkers for decision making in colon cancer treatment.

本研究旨在评估Toll样受体4（Toll-like receptor 4, TLR4）/核因子κB（Nuclear Factor-kappa B, NF-κB）通路的表达、多态性与结肠癌之间的关联。本研究对结直肠癌患者与健康对照的血液样本开展了TLR4基因位点rs4986790、rs10759932、rs10759931及rs2770150的基因分型检测。采用实时荧光定量PCR（real time PCR）对40对配对的正常结肠组织与结肠癌组织中的TLR4及炎性细胞因子表达水平进行检测，并通过免疫组化（Immunohistochemistry）法测定其蛋白表达水平。结肠癌组织中TLR4的高表达主要源于人体结肠内的细菌感染，可通过NF-κB介导通路诱导炎性细胞因子的急性分泌。此外，本研究明确证实TLR4 rs10759931多态性与结肠癌存在显著关联（比值比OR=0.086，置信区间CI=0.04~0.18，P<0.00001）。该多态性在全人群中均有分布，无性别或年龄群体特异性。与之相反，rs2770150多态性与50岁以上女性的结肠癌发病相关，且与绝经后女性体内雌性激素水平降低密切相关（OR=0.188，CI=0.074~0.48，P<0.00084）。rs10759932与rs4986790则未显示与结肠癌存在关联。本研究数据表明，TLR4单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）有望成为结肠癌临床治疗决策的潜在生物标志物。