Research On The Clinical Significance Of RIPK4 In Epithelial Ovarian Cancer And Its Role And Mechanism On The Biological Functions Of Ovarian Cancer Cells

Background:Epithelial ovarian cancer(EOC)is the most common ovarian cancer.The prognosis of EOC is very poor because the most patients have been diagnosed with the advanced EOC.At present,the treatments of advanced ovarian cancer mainly depend on the cytoreductive surgery combined with platinum-based adjuvant chemotherapy.The Antiangiogenic drugs and PARP inhibitors have been recommended for maintenance therapy of advanced ovarian cancer in recent years,but the overall survival of patients have been not improved significantly.About 70%of patients with advanced EOC suffered the treatment failure because of the recurrence as the result of the migration of EOC.So the new potential therapeutic targets for the advanced EOC are necessary.Method:The Gene sequencing is an effective method to screen the potential gene targets,and the databases based on gene sequencing dates provide an excellent platform for us to find the new therapeutic targets for EOC.Firstly,the targeted genes with differential expression between the normal and the ovarian cancer and related to the prognosis of EOC was screened out based on the GEO and DEPIA databases.And then the TCGA、Oncomine and KM plotter databases were adopted to identify the clinical role of these candidates.Next,SKOV3 cell,a common human ovarian cancer cell line was used to establish the ovarian cancer cell model with low expression of the target genes through the siRNA technology for studying the influence of suppression of RIPK4 on growth,apoptosis,migration or invasion and vascular mimicry of skov3 cell and the regulation between RIPK4 and EMT.Results:Lastly,RIPK4 was selected as our research objective among these target genes screened out by databases.Based on these databases,we found that the RIPK4 overexpressed in ovarian cancer compared with the normal,moreover,the same consequence was observed in different pathological subtypes of ovarian cancer,including serous,mucision and clear cell.The Kaplan-Meier survival curves showed that the high-expression of RIPK4 could obviously reduced the overall survival(OS)and post progression survival(PPS)of patients with advanced ovarian cancer,meanwhile the results of multivariate Cox proportional risk regression model for overall survival suggested that high-expression of RIPK4 significantly increased the risk of death in patients with advanced ovarian cancer(HR 1.473;95%CI 1.089-1.991;p-value=0.012).Moreover,the expression of RIPK4 was related to the FIGO stage of patients(p-value=0.017),and the proportion of patients with the high-expression of RIPK4 increased as the FIGO stage rose.What more,according to the results of functional experiments,we discovered that the suppression of RIPK4 significantly inhibited the migration and invasion,growth and vascular mimicry of SKOV3 in vitro and suppressed its implantation in abdominal cavity of nude mice,but had no inducement on apoptosis.Meanwhile the knock-down of RIPK4 suppressed the process of epithelial-mesenchymal transition(EMT)of ovarian cancer cell by promoting the expression of E-cadherin and inhibiting the expression of N-cadherin.EMT is an important biological process for epithelial-derived cancer cells to acquire the ability of metastasis and invasion.Therefore RIPK4 could induce the EMT of ovarian cancer by regulating the expression of E-cadherin and N-cadherin,to contribute to the migration and invasion of ovarian cancer cells eventually.Conclusion:We studied and explained the clinical roles of RIPK4 on epithelial ovarian cancer.Compared with the normal ovarian tissue,the expression of RIPK4 increased in various pathological sub-types of ovarian cancer.In addition,the expression of RIPK4 was connected with clinical stage and high expression of RIPK4 leaded to the poor prognosis for patients with serous ovarian cancer.And then we described the association between RIPK4 and the EMT progression in ovarian cancer cells for the first time and discovered that RIPK4 could induce EMT by regulating the expression of E-cadherin negatively and N-cadherin positively to influence the metastasis of ovarian cancer cell.Whats more,RIPK4 could be beneficial for the growth and vascular mimicry of ovarian cancer cell.Given the above results,RIPK4 could be considered as a potential therapeutic target for epithelial ovarian cancer.