| Despite the skillful surgical techniques and improvements in combined chemotherapy, epithelial ovarian cancer (EOC) still remains the leading cause of death in gynecological malignancies with five year survival rates of45%, and30%for patients with advanced stage. The main reason for failure of treatment and death is that a majority of cases are diagnosed at advanced stage of disease and most of them are liable to relapse and do not successfully respond to chemotherapy after primary treament. Glycogen synthase kinase-3(GSK-3) is a serine/threonine kinase that known to play an important role in the tumorigenesis beyond its original function of glycogen synthase regulation. But its effect on ovarian cancer is still unclear,In the present study, we first collected the epithelial ovarian cancer cases with complete clinical and five year follow up data. Immunohistochemistry was used to detect the expression of GSK-3α/β and pGSK-3α/β(Tyr279/216). We analysised the associations between GSK-3α/β and pGSK-3a/(3(Tyr279/216) expressions with clinicopathological factors, chemotherapy response and prognosis. Secondly, we investigated the influences of GSK-3inhibitor--Licl alone or combination with paclitaxel on ovarian cancer cell in vivo, and detect the expression of GSK-3and its downstream moleculors in ovarian cancer xenograft tissues to explore the possible mechanism. This study was aimed to provide a preliminary experimental basis for exploring new strategies to the treatment of ovarian cancer. Part Ⅰ Expression of GSK-3in epithelial ovarian cancers and their clinical significanceObjectives:To investigate the expressions of GSK-3α/β and pGSK-3α/β (Tyr279/216) in epithelial ovarian cancers and to analysis their correlation with clinical-pathological parameters, chemotehrapy response and prognosis.Methods:Immunohistochemistry were used to detect the expressions of GSK-3α/β and pGSK-3α/β and their correlation with clinical-pathological parameters, chemotehrapy response and prognosis were anaiysised.Results:(1).The expression of GSK-3α/β and pGSK-3α/β in epithelial ovarian cancer were signifieandy higher than that in benign tumors(P<0.001).(2).The expression of GSK-3α/β in ovarian cancer was associated with tumor stage(P=0.001), residual tumor mass(P=0.007) and preoperative serum CA125level(P<0.001).(3). The expression of pGSK-3α/β in ovarian cancer was associated with tumor stage(P=0.001), residual tumor mass(P=0.009) and preoperative serum CA125level(P=0.005).(4). Higher levels of pGSK-3α/β (Tyr279/216) expression were observed in non-responders than in responders (P=0.003).(5). Univariate survival analysis reavealed that tumor stage(P<0.001, P<0.001), residual tumor mass(P<0.001, P<0.001), preoperative serum CA125level(P<0.001, P<0.001), chemotherapy with or without taxol(P=0.039, P<0.001) and higher expression of GSK-3a/(3(P=0.023, P=0.001) and pGSK-3α/β (Tyr279/216)(P=0.018, P=0.007) were associated with poor prognosis for disease-free and overall survival. In the multivariate analysis, tumor stage(P<0.001) and chemotherapy with or without taxol(P=0.041) were independent risk factors for disease-free survival, whereas tumor stage(P<0.001), chemotherapy with or without taxol(P<0.001) and GSK-3α/β expression(P=0.027) were independent risk factors for overall survival.Conclusion:GSK-3α/β may play an important role in progression of EOC and can be used as an important prognostic factor for survival of patients with EOC. Prat II Effect of Licl alone or combined with paclitaxel on ovarian carcinoma cells in vivoObjectives:To investigate the effect of GSK-3inhibitor Licl alone or combined with paclitaxel on ovarian cancer cell in vivo.Methods:Human ovarian xenograft models were established with nude mice and were randomly divided into4groups, namely, the control group, Licl group(340mg/kg.ip), paclitaxel group(20mg/kg, ip), and a combination group(Licl and paclitaxel). The volumes and weight of tumor mass were detected and the tumor inhibitory rates were calculated. Immunohistochemical assay was used to examine the expression of GSK-3α/β,pGSK-3α/β(Tyr279/216) and their downstream moleculors caspase-3protein.Results:(1)The tumor growth of ovarian carcinoma model after different treatment:the growth of tumors in Licl,paclitaxel and combination treated groups was inhibited compared to the control group,especially in combination treated group.(2)The inhibition rate of tumor growth:the inhibitory rate of tumor growth in Licl,paclitaxel, and combination treated groups were56.60%,68.7%and95.87%,respectively. There were significant difference among these three groups.(3)Immunohistochemistry results:the expression levels of pGSK-3α/β(Tyr279/216) in Licl and combination treated groups was significantly lower than those of control and paclitaxel groups, and caspase-3expression of the combination treated group was significantly higher than those of control,Licl and paclitaxel groups.Conclusion:GSK-3inhibitor Licl alone or combined with paclitaxel had a significant inhibition effect of tumors growth in vivo, and the inhibition effect of combined group is better than the only paclitaxel treated group, increased apoptosis may be one of the mechanism that Licl enhance the cytoxcity of paclitaxel. |
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