Expression And Clinical Significance Of Human Cytomegalovirus IE And Pp65 In Epithelial Ovarian Cance

Ovarian cancer is a common malignant tumor of the female reproductive system,the incidence of which among gynecological cancer is the third,but the mortality ranks the first.It has the characteristics of high malignancy,rapid development,easy to recur and poor prognosis.Among various types of ovarian cancer,epithelial ovarian cancer(EOC)is the most common,accounting for 85%-90% of the ovarian cancer.Often diagnosed at an advanced stage,the 5-year survival rate of ovarian cancer varies 30% to 40%.During recent years,the idea that microbial infection-induced chronic inflammation may serve a marked function in inducing carcinogenesis has been discussed.The female pelvic cavity can contact pathogens through the genital tract.So infectious pathogens may play a potential role in the development of ovarian cancer.Human cytomegalovirus(HCMV)belongs to ?-herpesvirus.The relationship between HCMV and human diseases has been studied in many aspects.It was found that HCMV DNA or mRNA was detected in tumor tissue samples,and the positive rate of HCMV markers detected in serological samples was significantly higher than that in normal controls.Many studies have shown that HCMV infection is related to the formation and progression of gastric cancer,breast cancer,colorectal cancer,glioma and other tumors.As a transcription factor,the immediate early protein(IE)expressed in HCMV infected cells regulates the gene expression of virus and host cells;as an immune regulatory protein,HCMV tegument protein 65(pp65)helps virus escape the recognition and killing of infected cells by T cells.However,the relationship between HCMV infection and gynecological tumors,especially ovarian cancer,has not been studied.ObjectiveThe aim is to detect the expression of HCMV IE and pp65 in epithelial ovarian cancer and ovarian benign cystadenoma;to analyze the correlation between the expression of HCMV proteins and the general clinical characteristics such as age,initial CA125,tumor pathological type and FIGO stage;to analyze the influence of HCMV infection on the prognosis of patients.The objective of our study is to understand the possible role and mechanism of HCMV in the occurrence and development of epithelial ovarian cancer,and to reveal the influence of HCMV infection on the prognosis of patients.MethodsIn this study,different types of epithelial ovarian cancer tissues were selected as the study group,and benign ovarian cystadenoma tissues were selected as the control.Immunohistochemistry was used to detect the expression of HCMV IE and pp65 intissues from the histological level;the correlation between the expression of HCMV IE and pp65 and the general clinical characteristics such as age,initial CA125,tumor pathological type and FIGO stage was analyzed;the influence of HCMV infection on the prognosis of patients was analyzed.SPSS 20.0 was used to analyze the data.Kaplan-Meier method was used to construct survival curve and analyze the influence of HCMV infection on the prognosis of patients.Univariate and multivariate Cox proportional hazards regression model was used to assess the independent predictive factors.P <0.05 was considered significant.Results1.HCMV IE,pp65 expression in epithelial ovarian cancerIn 66 cases of epithelial ovarian cancer,82% of the tissues showed positive expression of HCMV IE protein,while in 30 cases of benign ovarian cystadenoma,36%showed positive expression.The positive expression of HCMV pp65 protein was found in97% of the tissues and 63% in 30 cases of ovarian benign cystadenoma in the control group.The proteins are mainly located in the nucleus and/or cytoplasm.But there was no significant difference between the expression of IE and pp65 protein and age,initial level of CA125 and the pathological type of tumor.2.The relationship between HCMV IE,pp65 expression and the stage of EOCIn this study,there were 8 cases of early stage ovarian cancer(FIGO I-II)and 58 cases of late stage ovarian cancer(FIGO III-IV).HCMV IE protein was extensively expressed in 25%(2/8)EOC of stage I and II,and in 66%(38/58)EOC of stage III and IV.There was a high expression of HCMV IE protein in the nucleus and cytoplasm of EOC tissues in the late stage,and the intensity of IE protein increased significantly in advanced stage(P = 0.0279).HCMV pp65 protein was extensively expressed in 38%(3/8)EOC and 64%(37/58)EOC.Although the proportion of HCMV pp65 protein extensively expressed in EOC tissues in the late stage was elevated,there was no significant difference(P = 0.1537).3.The relationship between HCMV IE,pp65 expression and neoadjuvant chemotherapy before surgeryIn this study,34 EOC patients underwent primary debulking surgery and cytoreductive surgery,32 patients underwent interval debulking surgery after NACT.It was found that 75%(24 / 32)of 32 patients with NACT showed extensive expression of HCMV IE protein,while only 47%(16 / 34)of 34 patients without NACT showed extensive expression(P = 0.0202).69%(22 / 32)patients with NACT showed extensive expression of pp65,and only 53%(18 / 34)patients without NACT showed extensive expression(P = 0.1890).4.The relationship between HCMV IE,pp65 expression and prognosis of epithelial ovarian cancerUsing Kaplan-Meier survival analysis,we found that the OS of extensive expression of IE group was significantly shorter than that of focal expression or negative group,the difference of which is statistically significant(39 vs.41 months,P = 0.03);the OS of extensive expression of pp65 group was shorter than that of focal expression or negative group,but there was no statistical difference(40 vs.42 months,P = 0.37).To determine whether HCMV IE expression was an independent risk factor for the OS of EOC patients,we conducted both univariate and multivariate analyses.FIGO stage(P = 0.024)and HCMV IE expression(P = 0.032)were prognostic factors for OS in patients with EOC,shown from univariate analysis.Furthermore,the multivariate analysis indicated that HCMV IE expression(P = 0.034)was independent prognostic factors for OS.Conclusions1.The expression of HCMV IE and pp65 in EOC was higher than that in ovarian cystadenoma.2.The expression of HCMV IE and pp65 protein in EOC was not correlated with age,CA125 level and tumor pathological type.3.The extensive expression of IE protein in HCMV is related to the tumor stage of EOC.The extensive expression rate of IE protein in EOC tissue in late stage is significantly higher than that in EOC tissue in early stage.4.The extensive expression rate of HCMV IE protein in EOC tissue before neoadjuvant chemotherapy is significantly increased.Neoadjuvant chemotherapy may reactivate the latent HCMV in tumor.5.FIGO stage and extensive expression of HCMV IE are the influencing factors of OS in EOC patients,and the extensive expression of HCMV IE protein is an independent risk factor of OS.HCMV infection and the expression of IE and pp65 protein are related to the occurrence and development of EOC,but the effect of HCMV infection on the inflammatory response and biological behavior of ovarian cancer cells is a complex process,and the exact mechanism of tumor regulation in epithelial ovarian cancer needs further study.