Immunohistochemical Expression Of The Biomarkers Related To Tumor Invasion And Metastasis In Human Ovarian Carcinoma

Background Ovarian carcinoma is the third most common malignancy in the female reproductive system.Due to the location in the pelvic cavity,ovarian carcinoma is often clinically latent and very difficult to be diagnosed in the early disease stage.Most of the patients are found to have widespread abdominopelvic dissemination,even distant metastasis at the first visit.Therefore,ovarian carcinoma belongs to the most fatal malignant tumor in the female reproductive system.The patients with ovarian carcinoma usually have poor prognosis.Although the current treatment is developed,the patient’s five-year survival rate in the last three decades has not been significantly improved because of the significant abilities of tumor invasion and migration.Hence,there is an important clinical significance on the further studies of mechanisms about invasion and metastasis in ovarian carcinoma.The deepen knowledge of biomarkers which can predict the prognosis of patients with ovarian carcinoma become an urgent need.In recent years,there are numerous researches involving the molecular mechanisms of tumor invasion and metastasis,which mainly focus on epithelial-mesenchymal transition,cell adhesion,inflammatory tumor microenvironment,and so on.However,among the different types of neoplasm,the results of the biomarkers related to aforementioned mechanisms on tumor invasion and metastasis are usually controversial.Moreover,in ovarian carcinoma,not only it is rarely documented on the comparative analysis of the biomarkers in primary tumors and their paired metastatic tumors,and the correlations between the expression of the biomarkers and the patients’ clinicopathological characteristics or prognosis,but also some results are even disputable.In this context,we constructed ovarian carcinoma tissue microarrays and investigated the expression of E-cadherin,N-cadherin,β-catenin,p120 catenin,vimentin,CD68 and CD163 in human ovarian carcinoma by immunohistochemical(IHC)staining.In order to find the biomarkers that might predict the prognosis of the patients with ovarian carcinoma,the expression of these biomarkers in primary tumors and their paired metastatic tumors,and the correlations between the expression of the biomarkers and the patients’ clinicopathological characteristics or prognosis were respectively analyzed.Objective 1.To investigate the expression of E-cadherin,N-cadherin,β-catenin,p120 catenin,vimentin,CD68 and CD163 in the primary and their paired metastatic lesions of human ovarian carcinoma.2.To analyze the correlations between the expressions of E-cadherin,N-cadherin,β-catenin or p120 catenin and clinicopathological features or prognosis in the patients with ovarian carcinoma.Methods1.A total of 281 cases of patients with ovarian carcinoma in the department of pathology in Xijing Hospital,the Fourth Military Medical University,from January 1999 to August 2014,were collected and the tissues microarrays were established.The average age of patients with ovarian carcinoma is 51.66 years(15-78 years).Based on 2014 WHO classification of ovarian carcinoma,these cases included high-grade serous carcinoma(225 cases),endometrioid adenocarcinoma(16 cases),low-grade serous carcinoma(12 cases),mucinous adenocarcinoma(15 cases),clear cell carcinoma(10 cases),malignant mixed müllerian tumor/ carcinosarcoma(3 cases).According to 2014 FIGO staging,the patients’ tumor staging was divided into four groups including stage I(26 cases),stage II(24 cases),stage III(173 cases),stage IV(43 cases),and unknown stage(15 cases).Among 281 cases,there were 133 cases with paired primary and metastatic specimens and 148 cases with follow-up data.2.The expression of E-cadherin,N-cadherin,β-catenin,p120 catenin,vimentin,CD68 and CD163 were detected in the tissues of ovarian carcinoma by Max Vision? HRP IHC staining.3.The IHC results of E-cadherin,N-cadherin,β-catenin,p120 catenin and vimentin in the paired primary and metastatic tumors were analyzed by Pearson χ2 test.The difference between CD68 and CD163 positive macrophages in the paired primary and metastatic lesions were analyzed by t-test.The correlations between E-cadherin,N-cadherin,β-catenin or p120 catenin and the patients’ clinicopathological data were further analyzed by Pearson χ2 test.The correlations among the expressions of E-cadherin,β-catenin,p120 catenin and N-cadherin were analyzed by Spearman analysis.4.The survival curves of E-cadherin,N-cadherin,β-catenin and p120 catenin were drawn by Kaplan-Meier method.The correlations between the expression of E-cadherin,N-cadherin,β-catenin or p120 catenin and survival were analyzed by Log-rank method.Cox’s proportional hazards regression model was used to analyze the independent predictive factors in the patients with ovarian carcinoma.Results 1.There were significantly difference in the IHC expression of N-cadherin(P = 0.018)or β-catenin(P = 0.018)between the primary and paired metastatic tumors.The expression of N-cadherin in metastatic lesions was significantly higher than that in primary lesions.Conversely,the expression of β-catenin in metastatic lesions significantly decreased in comparison with the primary lesions.2.The expression of N-cadherin in ovarian carcinoma was correlated with FIGO staging (P = 0.034),histological type(P < 0.001)and tumor grade(P = 0.004).Similarly,the expression of p120 catenin was correlated with FIGO staging(P =0.043),histological type(P < 0.001),and tumor grade(P < 0.001).The higher expression of N-cadherin and lower expression of p120 catenin were more common in the advanced(FIGO II-IV)ovarian carcinoma,high-grade serous carcinoma,and high grade ovarian carcinoma.3.The patients with lower expression level of β-catenin(P = 0.008)or p120 catenin(P = 0.006)in ovarian carcinoma tissues had shorter overall survival duration than those of higher expression level.The multiple factor analysis revealed that both FIGO stage and the expressions level of β-catenin(P = 0.004)or p120 catenin(P = 0.016)were independent predictive factors in overall survival duration.4.There were significant correlations between the expressions of E-cadherin and β-catenin(P = 0.005),β-catenin and p120 catenin(P < 0.001),E-cadherin and p120 catenin(P < 0.001),N-cadherin and β-catenin(P = 0.002)by Spearman analysis.Conclusion 1.Compared with the paired primary lesions,the tumor cells in the metastatic lesions have the increasing expression of N-cadherin and the decreased β-catenin,which may suggest that the metastatic tumor cells may have significant abilities of invasion and migration.2.There are significant correlations between the expression levels of β-catenin or p120 catenin with overall survival duration in the patients with ovarian carcinoma.In concordance with this result,both β-catenin and p120 catenin may be the potential biomarkers that can predict the prognosis of the patients with ovarian carcinoma.3.Given a critical role of cadherin catenin complex(CCC)in ovarian tumorigenesis,invasion and metastasis,a comprehensive evaluation to the expression level of E-cadherin,β-catenin and p120 catenin,which are involved in the formation of CCC and regulate the adhesion of cells,may be useful in providing a reference for tumor biological behavior and clinical prognosis.