Theclinical Significance Of CKS2 In Epithelial Ovarian Cancer

Background and objectives:Ovarian epithelial cancer comprises heterogeneous types of tumors that display a wide clinical spectrum ranging from limited and well differentiated local lesions to invasive and poorly differentiated malignant carcinomas, which reveals the main challenge in its diagnosis and treatment. Attributing to symptoms associated with late-stage disease and suboptimal diagnostic modalities, Ovarian epithelial cancer costs the largest proportion of tumor-related mortality among all gynecologic malignant tumor, hence, the poor prognosis could be improved by a more profound understanding of its molecular pathogenesis, which may ultimately pay back to identification of new biomarkers available for approaching its early diagnosis, and development of individualized targeted therapies.Cyclin dependent-kinase subunit proteins (Cks) are initially identified through their prominent abilities for genetically suppressing defective alleles of the cyclin dependent kinases (CDKs) of either fission or budding yeast. Subsequent antique investigations demonstrated that these two sufficiently conserved small (9-18 kDa) orthologs were ubiquitously expressed in mammals and possibly other vertebrates and could directly bind to CDK/cyclin complexes, hence the designation Cks. Up to now, neither of these orthologous proteins act as inhibitors nor activators in the classic sense actually, but preferring adapt roles in mediating CDK functions about cell cycle.Disorganized expression of Cks2 has been associated with oncogenic roles for decades, the precise function of Cks2 remained poorly understood. Up to now, whether Cks2 is overexpressed in ovarian epithelial cancer, and if yes, whether and how aberrantly expressed Cks2 contributes to ovarian epithelial cancer initiation and progression remain to be characterized. In this observational retrospective study, expression of cks2 was measured in patients with a pathological diagnosis of ovarian epithelial cancer. In addition, relationship between CCNE1, P53 and Cks2 is explored with IHC.Methods:(1) Expression of cks2 was measured in patients with a pathological diagnosis of ovarian cancer and normal ovarian or fallopian tube samples using real-time reverse transcription polymerase chain reaction nd western blot.(2) Expression levels of Cks2 were detected in ovarian epithelial carcinomas by immunohistochemistry with streptavidin-perosidase. Through retrospective case analysis, the result was analyzed combing with the clinical situation and the follow-up results using SPSS 20.0 statistical software.(3) Validating the expression of Cks2, P53 and CCNE1 in ovarian serous cancer cases with immunohistochemistry, the result was analyzed with SPSS 20.0 statistical software.Results:(1) Expression levels of Cks2 were both significantly increased in ovarian epithelial tumors. Remarkably, a significant difference of mRNA among HG-SOC and non-high grade serous ovarian cancers (non-HG-SOC) was also revealed. In addition, the Cks2 expression in normal tubal fimbrias was below the detection limit with western-blot.(2) High expression rate of Cks2 protein was significantly higher in serous ovarian cancers (62.7%) than in endometrioid ovarian cancers (52.3%), mucinous ovarian cancers (41.7%) and clear cell ovarian cancers (8.3%). These results suggest that variation of Cks2 of different degrees was revealed in different types of ovarian epithelial tumors. Expression of Cks2 signatures predominated in the fimbriae (10-30%) and targeted secretory cells, rather than ciliated cells.(3) Cks2 correlated with the clinical stage of ovarian serous carcinoma (P <0.05).Existent correlation of Cks2 and ascites of patients, the existence of parametrial invasion, as well as the scope of the relevant residual tumor after surgery.Analysis showed that patients with low levels of Cks2 survival significantly longer compared to that patients with high levels of Cks2.(4) We revealed a synergistic role with mutant P53 in a statistically meaningful way with analyzing results of immunohistochemistry, thus put forward the hypothesis that Cks2 play a synergisitic role with mutant P53 responded to inducing up-regulation of CCNE1 of which amplification is associated with poor outcome.Conclusion:(1) The investigation of a possible clinical role of CKS2 points out the ability to generally discriminate between normal and OEC, or limited and invasive OEC, when singularly considered.(2) Cks2 may affect the development of ovarian cancer correlating with the clinical stage of ovarian serous carcinoma, ascites of patients, the existence of parametrial invasion, as well as the scope of the relevant residual tumor after surgery. We couldpredict the prognosis of patients with Cks2 as an independent element.(3) The ability of contributing to the development of ovarian cancer of Cks2 may be related to the interaction with the P53 protein and CCNE1 contributing to DNA injury.