论文部分内容阅读
Objective: Visfatin,a newly discovered adipocytokine,is thought to play a role in pathogenesis of metabolic-syndrome-related-cancers.Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrialcarcinoma.Methods: A total of 234 EC patients were included in this study.Serum visfatin,metabolic and anthropometric parameters were measured in EC patients and controls.The correlation between clinicopathological variables and visfatin in EC tissues and the prognostic value of visfatin for overall survival was evaluated,We investigated the effect of visfatin on endometrial carcinoma cell proliferation,cell cycle,and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells.We also assessed the effect of visfatin on tumour growth in vivo.Results: Serum levels of visfatin were significantly higher in EC patients than in controls (P<0.05).In univariate and multivariate logistic regression models,a positive association between EC and serum visfatin,BMI,waist-to-hip ratio,diabetes,and hypertension was evident (P<0,05),Visfatin expression was significantly higher in EC tissue than in normal endometrial tissue (P=0.00 1).Moreover,serum visfatin levels were significantly positively correlated with tissue expression of visfatin in EC patients (P<0.05).High visfatin expression in EC tissues was significantly associated with advanced FIGO stage (P=0.016) and myometrial invasion ≥ 1/2 (P=0.023).The overall survival rate of EC patients was significantly higher in the group with negative visfatin expression than with positive visfatin expression (F=0.035).Visfatin stimulated the proliferation of both Ishikawa and KLE cells,and visfatin treatment promoted G I/S phase progression and inhibited endometrial carcinoma cell apoptosis.Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice.Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining,which revealed much stronger positive signals for Ki-67 with over-abundant visfatin.Western blot analysis revealed that insulin receptor (IR),insulin receptor substrate (IRS) 1/2 and key components of the phosphoinositide 3-kinase (P13K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) 1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin.Treated cells showed increased C-MYC and cyclin D I and reduced caspase-3 expression.The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the P13K inhibitor LY294002 and MEK inhibitor U0126.Conclusions: Visfatin is a potential serum biomarker and prognostic factor for EC that may indicate high risk for EC and EC progression.Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and P13K/Akt and MAPK/ERK signalling.Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma.