Expression Of Phosphorylated Protein Kinase B And PTEN In Ovarian Epithelial Cancers

Background and ObjectiveEpithelial ovarian cancer(ovarian cancer, EOC) is the leading cause of death from gynaecologic cancer. It can not be diagnose in early stage, at the same time, it's easily metastatic with poor prognosis. The biological mechanism of ovarian cancer is still unclear. Recent researchs showed that the carcinogenesis and progression of many kinds of carcinomas including ovarian cancer are related with signal pathways. The abnormity of these pathways are correlative with malignant behavior and poor prognosis of carcinomas. Protein kinase B(PKB), in other words, named AKT is a kind of Ser/Thr kinase. At present, three kinds of PKB have been found: PKBα/β/γ(AKT-1/2/3). After AKT is activated, some target proteins which are related with apoptosis can be phosphorylated, so it plays a great importance in carcinogenesis and chemotherapy resistance. PI3K (phosphatidylinositol 3-kinase) are consist of P110 and P85 groups. AKT is a important target gene of PI3K. They constitute a important biology chain in promotin growth, inhibiting apoptosis and maintaining function of cells. The abnormity of PI3K/AKT pathway is associated with lots of carcinomas including gynecological carcinomas in carcinogenesis, progression, metastasis, building vascular and chemotherapy resistance. Phosphatase and tensin homolog deleted on chromosome 10(PTEN) is the only tumor suppressor gene with the activity of lipid phosphatase and albumen phosphatase in present. It has been established that PTEN can decrease the activation of AKT through inhibiting PI3K/AKT pathway, and modulate negatively the growth of cell. The absence of PTEN can activate PI3K/AKT pathway out of the way, make cells to avoid apoptosis and lead to carcinogenesis. But present researches only detected the expression of p-AKT and PTEN in ovarian tissues. The reports about the relationship between their expression and pronosis of ovarian cancer are few. So we detected the expression of p-AKT and PTEN in ovarian cancer tissues by immunohistochemistry method, analysed their relationship and discussed their relationship with prognosis of ovarian cancer. In order to understand the possible molecular mechanism of ovarian cancer, supply possible prognosis indicators and offer a possible method for therapy.Materials and MethodsOne hundred and twenty-four paraffin-embedded blocks from the Department of pathology, the First Affiliated Hospital of Zhengzhou University from Junuray 2001 to Junuray 2006 were included in the study. These are consisted of 12 cases of normal ovary tissues(normal group); 20 cases of benign epithelial tumor tissues(benign group, 13 cases of serous cystadenoma, 7 cases of mucinous cystadenoma); 12 cases of borderline tumors tissues(borderline group, 8 cases of serous cystadenoma, 4 cases of mucinous cystadenoma); 80 cases of ovarian cancer tissues(ovarian group, 59 cases of serous cystadenocarcinoma, 21 cases of mucinous cystadenocarcinoma). The patients age were from 19 to72, median age was 45.5. There isn't obvious difference among these groups(P<0.05). Ovarian group: well differentiated tumor(grade 1) and moderately differentiated tumor(grade 2) were 52 cases, poorly differentiated tumor(grade 3) were 28 cases. The clinical stage of ovarian cancers was determined according to the International Federation of Obstetrics and Gynecology(FIGO) classification: stageâ… /â…¡were 36 cases, stageâ…¢/â…£were 44 cases. Lymph node metastasis were 29 cases. None of the patients had received any therapy before the ovarian cancer tissues were taken. Making the interview by calling or callback lasting 4-60 months until may of 2006. Detecting the expression of p-AKT and PTEN protein in ovarian tissuses by immunohistochemistry method to analyse their relationship and discuss their relationship with prognosis of ovarian cancer. Analysing data by statistic software SPSS 13.0. Discussing relationship between their expression and clinicopathological factors by Chi-Square Tests, their relationship by Spearman, clinicopathological factors of prognosis of ovarian cancer by univariate and multivariate analysis. The criterion of test wasα=0.05.Results 1. The expression of p-AKT and PTEN protein in different ovarian tissues. Thepositive rate of their expression in 80 cases of ovarian cancers, 12 cases of borderline tumors, 20 cases of benign tumor and 12 cases of normal tissues were 50.0%(44/80), 25.0%(3/12), 10.0%(2/20), 8.3%(1/12) and 45.0%(36/80), 66.7% (8/12), 80.0%(16/20), 100%(12/12). There were significant differences among the expression of p-AKT and PTEN in different ovary tissues (P=0.000). The expression of p-AKT in ovarian cancer group was higher than in benign and normal groups(P<0.001). The expression of PTEN protein in ovarian cancer group was lower than in benign and normal groups(P<0.001).2. The relationship between their expression(p-AKT and PTEN protein) andclinicopathological factors. The positive rate of p-AKT in well, moderate differenttiation cancer group(G₁+G₂) was 44.2%(23/52). It is lower than that in poor differentiation cancer groups). The positive rate was 75.0%(21/28). There was significant difference between these two groups(P=0.008).3. The positive rate of PTEN protein expression in these groups were respectively55.8% (29/52) and 25.0% (7/28). There were significant difference between them (P=0.008). The positive rate of p-AKT protein expression in stageâ… /â…¡of EOC were respectively 33.3%(12/36) and 81.8%(36/44). There were significant difference between them(P=0.000). The positive rate of PTEN protein expression in these groups were respectively 52.8%(19/36), 27.3%(12/44). There were significant difference between them(P=0.020). The positive rate of p-AKT protein expression in positive or negative lymph node metastasis of EOC were respectively 62.1% (18/29), 31.4% (16/51). There were significant difference between them (P=0.008). The positive rate of PTEN protein expression in these groups were respectively 31.0% (9/29), 68.6% (35/51). There were significant difference between them(P=0.001). In age groups(<50 and >50 years old), cancer groups (serous cystadenocarcinoma and mucinous cystadenocarcinoma), ascites groups (positive and negative), there weren't significant difference(P>0.05).4. The correlation between the expression of p-AKT and PTEN protein in EOC.Their expression which were all positive or negative were respectively 11 cases. The expression of p-AKT was positive with negative expression of PTEN were 33 cases. The expression of PTEN was positive with negative expression of p-AKT were 25 cases. There was inversely correlation between the expression of p-AKT and PTEN protein in EOC(r=0.444, P<0.001). 5. In EOC, the relationship bewteen their expression and prognosis. When finished the experiment, there were 12 cases alive. The accumulative survival rate was 21.58% and the median survival time was 15 months. There were 8 cases alive in 32 cases of negative expression of p-AKT, 4 cases alive in 32 cases of positive expression of p-AKT. The accumulative survival rate was 27.3% and 15.6%, the median survival time were 25 and 15 months. Statistical significance was found between the two groups using Log Rank test(P =0.00079). There were 3 cases alive in 33 cases of negative expression of PTEN, 9 cases alive in 31 cases of positive expression of PTEN. The accumulative survival rate was 9.1% and 34.7%,the median survival time were 9 and 28 months. Statistical significance was found between the two groups using Log Rank test(P=0.000). They were divided into four groups: p-AKT-/PTEN+, p-AKT-/PTEN-, p-AKT+/PTEN- and p-AKT+ /PTEN+. Statistical significance was found among the four groups using Log Rank test(P=0.000). Univariate and multivariate analysis of clinicopathological factors of prognosis of EOC showed that clinical stage, histological differentiation, lymph node involvement, the expression of p-AKT and PTEN protein were related with the prognosis of EOC(P<0.05). The expression of PTEN protein and clinical stage are independent dangerous factors of prognosis of EOC(P<0.001).Conclusions1. The activation of AKT protein and the absence of PTEN were correlated with carcinogenesis, progression, invasion and metastasis of EOC.2. The expression of p-AKT is inversly correlated with that of PTEN in EOC.3. The expression of p-AKT was related with prognosis of EOC, but it isn't independent dangerous factor effecting the prognosis of EOC. PTEN and clinical stage are independent dangerous factors effecting the prognosis of EOC. It was revealed that detecting PTEN protein and clinical stage together may be a new way in estimating the prognosis of EOC.