Expression Of Toll-like Receptor4/Myeloid Differentiation Factor88Signals Correlates With Prognosis In Colorectal Cancer

Background&objective: In the world, colorectal cancer (colorectalcancer, CRC) ranks third in malignant tumors in cancer deaths fourth yearmore than100million new cases of colorectal cancer. In mainland China,the incidence of colorectal cancer is4.71%increase every year, far morethan2%of the international level. Pathogenesis has not been fullyelucidated cause difficulties on the diagnosis and treatment of itsincidence, one of the important causes of the high mortality. Toll-likereceptors (TLRs) are a natural immune-related antigen recognitionreceptor is expressed on the surface of immune cells, play a key role inthe immune response of the resisting invading pathogens. So far, at least11of Toll-like receptors have been shown to exist in mammals, werenamed as TLR1-11, and to participate in the immune and non-immunecells recognize pathogen-associated molecular patterns(pathogen-associated molecular patterns, PAMP) LPS(lipopolysaccharides, LPS), double-stranded RNA virus, and non-methylated CpG islands. Toll-like receptor signal transmissionthrough four adapter protein, ie, myeloid differentiation factor88(MyD88), MyD88similar adapter, Toll/IL1R domain adapter moleculeinduced interferon-, TRIF-related joint molecules. The stimulationTLRS lead to the activation of the nuclear factor-κB (nuclear factor-κB,NF-κB) and mitogen-activated protein kinase, which is essential TLRactivation the classic achievements: host innate and adaptive immuneresponse. Toll-like receptor-mediated innate immunity or acquiredimmunity can be used as an effective immune adjuvant, can be used intumor immunotherapy or combination therapy of tumors. Recently,however, a large number of domestic and international research evidenceto suggest that the functional expression of TLRs in many tumors. Manydomestic and foreign scholars in-depth research on the pathogenesis ofcolorectal cancer and found that the expression of Toll-like receptors(Toll-like receptor, TLRs) in colorectal cancer cells and tissues, a largenumber of domestic and foreign research that Toll-like receptors ontumor occurrence, development has an important influence, particularlyin tumors is associated with inflammation, such as liver cancer, coloncancer, gastric cancer, and cervical cancer. In the natural immune system,TLRs is an important part, but also with many domestic and foreignscholars study of the pathogenesis of tumor, and confirmed that theToll-like receptor4(Toll-like receptor-4, TLR4) signal transduction pathway have carcinogenic effects in vitro and in vivo. Myeloiddifferentiation factor88(myeloid differentiation factor88, MyD88) theTLRs signal transduction pathways important adapter protein, thecorresponding signal transduction pathways including MyD88-dependentpathway and non-dependent pathway. MyD88was able to be used as theTLR4signal transduction pathway is important downstream signalingfactor, because it contains a TIR domain. MyD88is closely related to theoncogenic pro-inflammatory response. In TRLs signaling pathway playsa key role. TRLs signal through MyD88activation of nuclearfactor-kappa B (NF-kappaB) signaling pathway, thereby activating thephosphatidylinositol3kinase/serine threonine protein kinase(phosphatei-dylinositol3kinase/serine-threonine kinase, PI3K/Akt) orcause a variety of cytokine release, and to promote the proliferation ofcolon cancer cells, inhibition of tumor cell apoptosis and immune escapemechanisms, resulting in the occurrence, development, invasion andmetastasis of colorectal cancer. In order to prove the role of TLR-4signaling pathway in colon tumor formation, we conducted a study incolorectal cancer (CRC) cells abnormal expression of TLR-4and MyD88expression levels and occurred in colorectal tumors, development,invasion, metastasis, and a detailed analysis of the close correlation withthe clinical outcomes. Materials&Methods:1. using immunohistochemical methods were used to detect theToll-like receptor4and myeloid differentiation factor88in a sample of101cases of colorectal cancer,10cases of adenoma samples,10cases ofadjacent normal mucosa tissue samples in paraffin-embedded biopsyexpression case.2. complete collection of colorectal cancer patients with clinical andpathological data, including the patient’s demographic information(gender, age) and tumor characteristics (anatomical site, histological type,vascular invasion, lymphatic invasion, lymph node metastasis, livermetastasis, peritoneal metastasis, TNM stage) and survival time. Theretrospective analysis of TLR-4and MyD88expression and colorectalcancer clinical and pathological features and prognosis, as well as TLR-4and MyD88correlation.3. Correlation with Pearson’s chi-square test or Fisher’s exact test,using Kaplan-Meier analysis and calculation of the single factor andsurvival, the use of the Log-rank test of significance of the differences,using the Cox proportional hazards model for multivariate survivalanalysis.Results:1. TLR-4and MyD88were expressed in all colorectal cancer tissue. 2. Compared to normal mucosa and adenoma, CRC organizationshigh19.8%of TLR4expression,22.8%of the high expression of MyD88.TLR4and MyD88expression and tumor metastasis were significantlycorrelated (P=0.0001, P=0.014). In univariate analysis of TLR4expression and shorter DFS (hazard ratio (HR):2.01;95%confidenceinterval (95%CI):1.10-4.27, P=0.018) and OS were significantlyrelated (hazard ratio (HR):1.61;95%confidence interval (95%CI):1.86-5.34, P=0.032). MyD88significantly higher expressionassociated with a shorter DFS and OS (HR:1.91,95%CI:0.98-4.18, P=0.028; HR:1.88,95%CI:1.12-5.67, P=0.019) was significantlyassociated the. TLR4and MyD88expression was significantly correlatedwith poor DFS and OS (HR:4.63,95%CI:1.86-11.79, P=0.001HR:4.44,95%CI:1.64-11.96, P=0.001). Multivariate analysis showed thathigh expression of TLR4(OS: adjusted HR:2.23;95%CI:1.18-3.87, P=0.0135) and MyD88(DFS: adjusted HR:2.1,95%CI:1.01-3.87OS:adjusted HR:4.12,95%CI:1.71-12.01, P=0.0011), P=0.0371;independent prognostic factors for OS. In addition, a significantly higherexpression TLR4/MyD88with shorter DFS (adjusted HR:1.87,95%CI:1.12-3.56, P=0.0231) and an OS (adjusted HR:6.12,95%CI:2.21-14.14, P=0.0001) and also significantly correlated.Conclusion: Our results show that a high TLR4and MyD88highexpression of liver metastases, and is an independent factor of poor prognosis in patients with CRC.