NPRLl2/RKIP/THY1Expressions And Clinical Significance In Low And High Grade Serous Ovarian Adenocarcinoma

Objective:Ovarian cancer is the most common cause of death amongwomen with gynecologic malignant tumor.The reason is unable to findeffective early diagnosis technology, and no effective treatments.According tothe dualism of ovarian cancer disease model and the theory of the origin ofovary, epithelial ovarian cancer is divided into two kinds of completelydifferent types:type Ⅰ and type Ⅱ. Through pathological and biologicalcharacteristics of the two types of ovarian cancer found that, generally type Iovarian carcinoma involves a stepwise progression from benign tumor toborderline (atypical) and then low-grade malignant tumor,and type II ovariancancer is directly off ovarian epithelial malignant cells by tubal fimbria. Type Iovarian cancer contain ovarian low-grade serous adenocarcinoma/ovarianlow-grade uterine endometrioid carcinoma/clear cell carcinoma/mucinouscarcinoma/transitional cell carcinoma. Most of Type I ovarian cancer is slowonset, often prodromal symptoms, most of early clinical and good prognosis,but is not sensitive to chemotherapy, prone to drug resistance.Early surgicalresection and main molecular pathway targeted drugs may be an effectiveadjunctive treatment of type I ovarian cancer. Type II ovarian cancer isincluding high-grade serous adenocarcinoma and high-grade endometrioidcarcinoma, undifferentiated carcinoma and malignant mesodermal mixedtumor (carcinosarcoma).It is the incidence of fast, prodromal symptoms,aggressive, mostly late clinical stage and poor prognosis, but more sensitive tochemotherapy, cytoreductive surgery and combination chemotherapy mainly.Ovarian serous adenocarcinoma (OSC) is the most common histologic type inovarian cancer, and the is most good application histological with dualismmodel type.Singer found that ovarian low-grade serous adenocarcinomaformed by benign→borderline→malignant process development, ovarian high-grade serous adenocarcinoma formed by ovarian serous adenocarcinomaserous tubal intraepithelial carcinoma directly. The mechanism of itsdevelopment has not yet been fully elucidated.The incidence of serous ovariancancer is a multifactorial, complex multi-step biological process.NPRL2/PDKlcomplexes was formed by NPRL2and PDK1.NPRL2/PDKl complexes inhibitPDKl activation.In addition, the composite also inactivate PDKl downstreamincluding ribosomal protein kinase Akt and P70inactivation, therebyimproving the sensitivity of tumor cells to anticancer drugs, especiallycis-platinum. RKIP (Raf kinase inhibitor prote) is a member of PEBPs. Yeungfound PEBP specific inhibition of the Raf-1activity, studies show that the lossof expression of RKIP decreased sensitivity to cisplatin, promoting tumor cellsmetastasis. THY1(Thymus cell antigen1) is the glycoprotein of a highlyglycosylated cell surface, THY1loss of expression promotes tumor cellsmetastasis. Studys showed that the P53abnormally high levels of expressionin ovarian serous adenocarcinoma of the high-grade, while expression normalin ovarian low-grade adenocarcinoma. Therefore, the discussion of thedifferences of the different grades serous ovarian adenocarcinomapathogenesis and biological behavior, reasonably effective treatment forovarian cancer is very necessary. In this study, using immunohistochemicalmethods to detect suppressor gene NPRL2/RKIP/THY1/P53proteinexpressions in low and high-grade ovarian serous adenocarcinoma tumor,combined with ovarian serous adenocarcinoma dualism comparative analysisof the differences in the expression and significance, while further detectingtheir expressions in ovarian serous cystadenoma, borderline cystadenoma andlow-grade serous adenocarcinoma. To further elucidate the pathogenesis oflow and high grade serous adenocarcinoma, and to provide a reference for theprognosis and treatment of low and high grade serous adenocarcinoma, and topredict prognosis and guide postoperative medication.Methods: The samples were all collected from the Second Hospital ofHebei Medical University from January2003to June2007, including61casesof serous adenocarcinoma specimens (20cases of low-grade and41cases of high-grade) after surgical resection and confirmed by pathology,47cases ofserous cystadenoma,9cases of Serous borderline cystadenoma,10cases ofnormal ovarian tissues and10cases of normal fallopian tube tissue. Using theimmunohistochemical staining to detect the expressions ofNPRL2/RKIP/THY1/P53. The potential role and clinical relevance ofNPRL2/RKIP/THY1/P53expression were contrastively analyzed in low andhigh-grade serous adenocarcinomas.Two-step method of Immunohistochemistry was used to detecte theexpression of NPRL2/RKIP/THY1/P53in high and low-grade serousadenocarcinoma, serous borderline tumor, serous cystadenoma, normalovarian epithelial tissue and normal oviduct tissue. Formalin-fixed,paraffin-embedded,4-mm tissue sections were prepared, and ElivisionTMplustwo-step method was performed. Other conditions remain unchanged, insteadof primary antibody in PBS as a negative control. SPSS13.0software wasused for statistical analysis, including X2test, Kaplan-Meier single factorsurvival analysis, Log-Rank test and the Cox multivariate survival analysis.Result:1The pathomorphological characteristics describedOvarian serous cystadenoma were cystic papillary or adenofibroma kind ofcysts or nipple surface coating monolayer similar oviduct ciliated cells of thetumor cells, hyperplasia and atypia. Ovarian serous borderline tumors werecysts or nipple surface coating epithelial cell hyperplasia, the level increased,disorganized, and nucleus atypical mild-moderate, a small amount of mitoticfigures. Serous adenocarcinoma cancer cells showed irregular tubular,papillary or solid arrangement, atypical mitotic and accompanied by largeamounts. Ovarian serous adenocarcinoma was divided into low-andhigh-grade groups according to atypia and mitosis count of cancer cells. Inlow-grade group, adenocarcinoma cells showed the same size, round oregg-shaped, uniform fine chromatin and mild-moderate atypia, and themitotic count less than≤12/10HPF. In high gade group, the cells haddisparity shape and sizes, with severe nucleus atypia (nuclear size differences ≥3:1), and the mitotic count more than12/10HPF. The stromal invasion werenot consider in both grades.2Expression of P53in ovarian serous adenocarcinomaP53positive expression rate of low grade serous ovarian adenocarcinomais25%, P53positive expression rate of high grade serous ovarianadenocarcinoma is78%. The P53positive expression rate in low grade serousadenocarcinoma is lower than in high grade serous ovarian adenocarcinoma(P<0.05).3NPRL2/RKIP/THY1expression in the low grade serous ovarianadenocarcinoma3.1NPRL2expression in low grade serous ovarian adenocarcinoma, Serousborderline cystadenoma and ovarian serous cystadenoma positive expressionrate were50%,55.6%and70.2%. From normal to low grade serousadenocarcinoma, NPRL2positive expression rate gradually reduced, statisticalanalysis showed that low-grade cancer with cystadenoma and normal groupthe difference was statistically significant (P<0.05), there was no statisticallysignificant difference between other groups.3.2RKIP expression in low grade serous ovarian adenocarcinoma,Serousborderline cystadenoma and ovarian serous cystadenoma positive expressionrate were60%,66.7%and83%.From normal to low grade serousadenocarcinoma, RKIP positive expression rate gradually reduced, statisticalanalysis showed that low-grade cancer with cystadenoma and normal groupthe difference was statistically significant (P <0.05), there was no statisticallysignificant difference between other groups.3.3THY1expression in low grade serous ovarian adenocarcinoma,Serousborderline cystadenoma and ovarian serous cystadenoma positive expressionrate were55%,55.6%and83%.From normal to low grade serousadenocarcinoma, THY1positive expression rate gradually reduced, statisticalanalysis showed that low-grade cancer with cystadenoma and normal groupthe difference was statistically significant (P<0.05), there was no statisticallysignificant difference between other groups. 4NPRL2/RKIP/THY1expression in the high grade serous ovarianadenocarcinoma4.1NPRL2in high grade serous ovarian adenocarcinoma in the positiveexpression rate of29.3%, compared with normal oviduct epithelium group nosignificant difference (P>0.05).4.2RKIP in high grade serous ovarian adenocarcinoma in the positiveexpression rate of17.1%, compared with normal oviduct epithelium groupdecreased obviously, the difference has statistics meaning (P <0.05).4.3THY1in high grade serous ovarian adenocarcinoma in the positiveexpression rate of14.6%, compared with normal oviduct epithelium groupdecreased obviously, the difference has statistics meaning (P <0.05).5Comparison between serous adenocarcinoma of high-grade and low-gradeTHY1positive expression rate in high-grade group was significantlylower than the low-grade group (P <0.05); RKIP in high-grade group of thepositive expression was significantly lower than the low-grade group(P<0.05).6The relationship of high and low-grade of serous adenocarcinoma survivalanalysis with NPRL2/RKIP/THY1expression6.1High grade serous ovarian adenocarcinoma in3years and5yearssurvival rates were respectively34.1%and12.2%. Low-grade serous ovarianadenocarcinoma3years and5years survival rate were respectively85%and70%. The low-grade and high-grade serous ovarian adenocarcinoma between3years and5years survival rate was different.(P<0.05)6.2In low grade serous ovarian adenocarcinoma, P53positive and negativeexpression of3year survival rates were respectively40%and100%, and5years survival rates were respectively20%and86.1%.To compare two groupswere different. NPRL2positive and negative expression of the3year survivalrates were respectively100%and70%.5years survival rates wererespectively100%and40%. the former indifference,the latter was different;RKIP positive and negative expression of the3year survival rates wererespectively91.7%and75%,5years survival rates were91.7%and37.5%respectively,the latter was different. THY1positive and negative expression of the3year survival rates were100%and66.7%respectively,5years survivalrates were90.9%and44.4%respectively, compared two groups all to bedifferent.6.3In high-grade serous ovarian adenocarcinoma, P53/RKIP/THY1positiveexpression and negative expression between the3years survival rate and the5-year survival rate are undifferentiated.7The relationship between NPRL2/RKIP/THY1expression and clinicalpathological featuresTHY1/RKIP protein expression in high-grade of ovarian serousadenocarcinoma was no correlation with peritoneal metastasis；THY1/RKIP/NPRL2protein expression in low-grade of ovarian serousadenocarcinoma was no correlation with peritoneal metastasis.8COX multi-factor survival analysis：Cox multivariate survival analysisshowed that in ovarian low-grade serous adenocarcinoma, only clinical stagewas the only important independent prognosis factor(P=0.001)(the independrisk coefficient was3.578).Conclusion:1The decrease or lost of NPRL2, THY1and RKIP protein expressionmay be involved in pathogenesis of low grade serous adenocarcinoma.2The decrease or lost of RKIP and THY1, but without NPRL2, showedthat it could play an important role in oncogenesis of high-grade serousovarian adenocarcinoma.3There was significant difference between high and low grade serousovarian adenocarcinoma in the RKIP and THY1positive expressionrate,proved that low-grade and high-grade formation may have differentmolecular pathway.43years and5years survival rate of high grade serous ovarianadenocarcinoma was significantly lower than the low-grade. The proteinexpression of three were nothing to do with survival in patients withhigh-grade, and was associated with survival for patients withlow-grade.Explaining that the protein expression of three were no correlation with prognostic judgment in patients with high-grade, but had certain value forthe prognosis of patients with low-grade judgment.5THY1/RKIP/NPRL2protein expression in ovarian serousadenocarcinoma was no correlation with peritoneal metastasis.6Cox multivariate survival analysis showed that in ovarian low gradeserous adenocarcinoma, clinical stage was the only important independentprognosis factor.