Expression And Significance Of COX-2, Ki-67, Survivin In Hepatocellular Carcinoma

Objective Cyclooxygenase(COX) is a key enzyme in synthesis of prostanoids. Two isoforms of this enzyme have been identified:COX-1 and COX-2.Recent studies have shown that COX-2 is closely associated with tumors, especially gastrointestinal cancer. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with increasing incidence in our country. So it is important for revealing carcinogens mechanism to further investigate the function of COX-2 in occurrence and progression of HCC. This can proviod new insight into treatment and prevention of HCC. The expression of the human Ki-67 protein is strictly associated with cell proliferation.The fact that the Ki-67 protein is present during all active phases of the cell cycle,but is absent from resting cells,makes it an excellent marker for determining the so-called growth fraction of a given cell population. Survivin is a newly discovered member of inhibitor of apoptosis protein(IAP). It is a bifunctional protein that surppress apoptosis and regulates cell division. One of the most significant features of survivin is that it is expressed in embryonic organs and thymus, but is undetectable in most terminally diferentiated normal tissues. Therefore, in the present study, we evaluated the expression of COX-2, Ki67 and survivin in HCC and examined the relationship of their expression with various clinicopathological factors and patient survival. We hope that it can throw line on the cause of HCC and provide preventive and therapeutic method for it. Methods The clinical, pathologic and follow-up information of patients with HCCfrom December 1998 to December 2000 in department of hepatobiliary surgery, Tianjin medical university cancer hospital was collected and reviewed. We conducted an immunohistochemical investigation of COX-2, Ki67 and survivin in paraffinmbedded sample of 105 HCC. Results were compared with sex, age, diameter of main nodule, number of nodules,tumor capsule, cirrhosis, AFP, Child-Pugh classification, histological grade, portal vein thrombosis (PVT), HBsAg, TNM stage of the patients respectively. Relationship among the expression of COX-2, Ki67 and survivin was analysed, so was the relationship between expression and their prognostic significance. Stastistical analysis was carried out using SPSS13.0. Results1. COX-2 protein was expressed in 77.1 % (81/105) of HCC, 82.3% (51/62) in adjacent non-tumor tissues;Ki67 protein was expressed in 43.8 % (46/105) and 11.3%(7/62) respectively;Survivin protein was expressed in 68.6%(72/105) and 27.4%(17/62) respectively. Here we show that by immunohistochemical staining that COX-2 protein lever was higher in the adjacent non-tumor tissues than in the tumors themselves,and the lever of expression of COX-2 in poorly-differentiated HCC(PD-HCC) was similar to that of well-differentiated HCC(WD-HCC). However, Ki-67 and survivin protein lever was lower in the adjacent non-tumor tissues than in the tumors themselves,and the lever of expression of them in PD-HCC was higher than that of WD-HCC. Abnormal expression of the three proteins correlated with PVT. The expression of the proteins in the group with portal vein thrombosis(PVT) was significantly higher than that in the group without PVT(COX-2:P=0.008;Ki-67J°=0.002;survivin:P=0.002).2. There were positive correlations between the expression of COX-2 and Ki-67 (rs=0.252, P=0.009) , between the expression of COX-2 and survivin Os =0.315, P=0.001) , and between the expression of survivin and Ki-67 (rs =0.226, P=0.021) . 3. The median survival time of COX-2 negative expression cases and positive expression cases were 83.9 and 31.3 months. The l-,3-,and 5-year overall survival of COX-2 negative expression cases and positive expression cases were 96%,88%,83%,and 75%,44%,35% respectively. The median survival time of Ki-67 negative expression cases and positive expression cases were 83.0 and 32.6 months.The l-,3-,and 5-year overall survival of Ki-67 negative expression cases and positive expression cases were 82%,63%,59%,and 78%,44%,28% respectively. The median survival time of survivin negative expression cases and positive expression cases were 81.6 and 29.3 months.The l-,3-,and 5-year overall survival of survivin negative expression cases and positive expression cases were 94%,79%,67%,and 74%,43%,36% respectively. The Kaplan-Meier survival analyze show that the survival rate of the patients with HCC is significantly different between groups with or without the expression of COX-2, Ki67 and survivin protein(COX-2: LogRank=14.049, P<0.001;Ki-67: LogRank=8.621, P=0.003;survivin: LogRank=10.413, P=0.001). Conclusions1. Our data suggest that COX-2 may play a role in the advanced stages as well as early stages of hepatocarcinogenesis , and both chemoprevention and chemotherapy of HCC by COX-2 specific inhibitors should be considered.2. The occurrence of HCC may be related with cell proliferation and apoptosis. COX-2 overexpression may play an important role in the pathogenesis of HCC by promoting cell proliferation and suppressing cell apoptosis.3. COX-2, Ki-67, survivin can increase tumor cell invasiveness, may promote thereccurence and metastatic potential of HCC.4 . The three proteins were significantly associated with patients overall survival.The expression of COX-2, Ki-67, survivin may be used as new targets for earlydiagnosis, treatment and evaluating prognosis of patients with HCC.