Prognostic Signigicance Of TLR4/MYD88Expression By Human Epithelial Ovarian Carcinoma Cells

BACKGROUND&PURPOSE:Drug resistance is a major cause of treatment failure in ovarian cancer. Toll-like receptors, key parts of the innate immune system, are being increasingly studied in cancer pathogenesis, influencing both tumour proliferation and chemoresistance. Recent evidence has identified that the contribution of Toll-like receptor4(TLR4)/Myeloid differentiation factor88(MyD88) signaling pathway to promote epithelial ovarian cancer (EOC) carcinogenesis, invasion and metastasis, and predicts a poor response to paclitaxel chemotherapy. EOC cells that express MyD88constitutively secrete pro-inflammatory cytokines and are resistant to paclitaxel, which is a known TLR-4ligand. Signaling via MyD88involves the early activation of nuclear factor-KB (NF-κB), which leads to the production of proinflammatory cytokines that promote proliferation. Moreover, TLR4/MyD88 signaling is able to induce the activationof the PI3K/Akt survival pathway, leading EOC growth and antiapoptosis. However, little is known about the clinicopathological factors and prognostic significance of TLR4and MyD88expression in EOC.The objective of this study was to investigate the prognostic significance of immunohistochemical detection of TLR4and MyD88expression and its association with clinicopathological factors in patients with EOC, to further optimize treatment strategies, to develop new chemotherapeutic agents and to evaluate prognostic significance of EOC.METHODS:1. TLR4and MyD88expression were examined by immunocytochemistry and Western-Blot in Human EOC cell lines (SKOV-3and A2780)2. TLR4and MyD88expression were examined by immunohischemistry in109specimens of ovarian tissues, comprising EOC (N=83), borderline tumors (N=9), benign cysts (N=9) and normal ovarian tissue (N=8).3. Information on patient demographics (age) and tumor features (pathology, histological grade, FIGO stage, lymph node metastasis, malignant cells in ascites, liver or lung metastasis, and residual tumor) was obtained from clinical and pathological records. The correlations between MyD88expression and clinicopathological factors and outcomes were analyzed. RESULTS:1. TLR4expression was detected frequently in all the ovarian tissues.2. Distinct MyD88expression was showed in EOC (64of83,77.1%), in borderline tumors (5of9,55.6%) and in benign cysts (3of9,33.3%), and normal ovarian tissue showed no MyD88expression.3. Univariate and multivariate analyses revealed that MyD88expression was an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) for EOC. Both DFS and OS rates in MyD88-negative EOC were significantly higher than in MyD88-positive EOC(P<0.0001and P=0.0031), and high MyD88expression was significantly correlated with tumor metastasis (P=0.0012)for EOC.CONCLUSION:Our data indicate that MyD88expression is a significantly poor prognostic factor for EOC. A better understanding of the role of MyD88expression in disease progression and outcome may be helpful for development of novel chemotherapies for patients with EOC.