| Backgroud：Epithelial ovarian cancer is the most common ovarian cancer, however,the highest fatality rate of malignant tumors of female genital organs is stillepithelial ovarian cancer.Epithelial ovarian cancer derives from the ovariansurface epithelium,ovarian serous carcinoma is the most commontype.Epithelial ovarian cancer also includes other types such as mucinouscarcinoma,endometrial cancer, uterine clear cell carcinoma and otherhistological types.In recent years, experts of department of gynaecology andmolecular pathology explored on the pathogenesis of ovarian serouscarcinoma, the molecular genetics and clinical pathologic morphology ofovarian serous carcinoma. Many studies suggest ovarian serous carcinoma hasthe dualism of incidence model:according to different pathogenesis of ovarianserous carcinoma,it will be divided into low grade and high grade ovarianserous adenocarcinoma,low grade ovarian serous adenocarcinoma is amulti-step process,through the pathogenesis of benign, borderline andmalignant tumor,it has precursor lesions; high grade ovarian serousadenocarcinoma directly originates from the ovarian surface epithelium orinclusion cyst,there are studies that shown it can also originate from thefallopian tube, there is no precursor lesions.The occurrence of tumor is a biological behavior which comprises ofmultiple genes and the mutation of multiple steps,and its process involves theactivation of oncogene and inactivation of tumor suppressor gene.Theformation of a variety of tumors is a process of the different genes mutationsand mutations of different intensity.The tumor is a genetic disease,itsbiological basis is the abnormality of gene.Oncogenic factors cause the mutation of somatic gene,meanwhile it also leads to the appearance ofabnormal gene and the disorder of gene expression,thus affecting thebiological activity and genetic characteristics of cell,so it formates the tumorcell which is different from the normal cell in morphology,metabolism andfunction.According to the model of the dualism pathogenesis of ovarian serouscarcinoma,low grade and high grade serous adenocarcinoma have differentgenetic basis,the low grade serous adenocarcinoma is mainly with themutation of KRAS or BRAF (reported about67%),however the high gradeserous adenocarcinoma is mainly with the mutation of P53gene.In thedeveloping process of the two types of serous carcinoma,there are also someoncogenes and tumor suppressor genes which play important roles, may alsobe the prognostic factors of ovarian serous carcinoma.In this article we willdiscuss the genes BRMS1,RIZ1and SATB1expression occurs in thedevelopment of the low grade and high grade serous adenocarcinoma,andexplore the difference of the two levels of serous carcinoma in thepathogenesis and prognosis, so in clinical work, we can use different diagnosisand treatment method to improve the survival rate of patients.BRMS1(breast cancer metastasis suppressor1)is one of the tumormetastasis suppressor genes which are found in recent years,according tosome reports,it correlates with breast cancer, melanoma and the metastasis ofnon-small cell lung cancer,and it also correlates with the metastasis of ovariancarcinoma. RIZ1(noblastoma protein-interacting zinc finger gene1) isseparated from the process which is the functional screening of Rb bindingproteins using Rb probe by Buyse et al. Research shows that it is ananti-oncogene protein molecule which comprises both a PR domain and zincfinger structure,and it can control the growth and inhibition of tumorcells.SATB1(special AT-rich sequence-binding protein1) is the tissuespecific nuclear matrix binding protein, it involves in the formation of seniorchromatin structure and the regulation of tissue specific geneexpression.SATB1can regulate the expression of genes by means of promoting chromatin remodeling,regulating of histone acetylation andmethylation in all the genetic level.According to the study, the tumor suppressor gene BRMSl and RIZ1have a certain reduction and absence in many human malignant tumor, SATB1gene plays an important role in the process of invasion and metastasis in avariety of malignant tumor. In this article,we studied the expression of thethree kinds of genes in the low grade and high grade ovarian serousadenocarcinoma,and further studied on the dualism pathogenesis of ovarianserous adenocarcinoma,so we can compare the pathogenesis and prognosis ofthe different levels of ovarian serous adenocarcinoma,and find the suitableprognostic indicators and treatment, and then improve the patients’ survivalrates of different levels of serous adenocarcinoma.Objective：In this study,we detected the expression change regulation ofBRMS1,RIZ1and SATB1in normal ovarian tissue,ovarian serous benigntumor,ovarian serous borderline tumor and low grade ovarian serousadenocarcinoma by using immunohistochemistry staining method,anddetected the expression changes of these three genes in normal fallopian tubeand high grade ovarian serous carcinoma.We studied the expression changesof these three genes and their possible regulation mechanisms in low gradeand high grade serous adenocarcinoma, and to explore its relationship withclinicopathological features which were of different grading ovarian serouscarcinoma and to judge the value of prognosis.At the same time we usedKaplan-Meier univariate survival analysis,and used Cox multivariate survivalanalysis to compare the effect on prognosis of degree,and to determine therisk coefficient of each factor, and to screen the related factors affecting theprognosis of the two types of ovarian serous carcinoma,and then judged theindependent predictor of prognosis factor and assessed each factor’s predictivevalue，and then evaluated and analyzed the prognosis value of gene BRMS1,SATB1and RIZ1protein expression in the different grades of ovarian serousadenocarcinoma. Methods1Research object: The127epithelial ovarian tumors investigated werecollected from patients diagnosed between2003and2007at the SecondHospital of HeBei Medical University,48of the tumors were serous benigntumors,18of the tumors were serous borderline tumors,and61of the tumorswere ovarian serous carcinomas with complete clinical information andfollow-up data.Fifteen normal ovarian tissues and10normal fallopian tubetissue were selected as control.2Immunohistochemistry: The protein expression of BRMS1, RIZ1,SATB1and P53were detected in low grade and high grade ovarian seroustumors with immunohistochemistry ElivisionTMplus two-step. Theimmunocytochemistry procession was also carried out strictly according tomanufacturer’s instructions. Negative control was carried out in identicalcondition excluding PBS, instead of antibody.3Survival analysis: A followed-up test was carried out in41high gradeand20low grade ovarian serous adenocarcinoma patients.We determined thecut-off point were36months and60months.Kaplan-Meier univariate survivalanalysis and Cox multivariate survival analysis were used in the study,andthen calculated the the sum survival rates in3and5years.The correlationbetween the factors which were SATB1,RIZ1,BRMS1,P53,clinicalstage,pathological grade, postoperative chemotherapy and prognosis wasanalysed, prognostic factors were screened,and the risk coefficient ofindependent factors were determined by Cox multivariate survival analysis.4Statistical treatment: The statistics analysis were carried out bySPSS13.0statistical package. In the study, enumeration data was comparedwith x2test，segmentation method was applied to compare two samples from aplurality of samples.Spearman rank correlation was used to analysis thecorrelation of all the indexes. Kaplan-Meier univariate survival analysis wasused to calculate the survival rate of the patients.Log-Rank test was used tocompare the significant different of survival rate, Cox multivariate survivalanalysis was applied to compare the effect on prognosis of degree, then to judge which were the independent predictive factors and predictive value ofeach factor, and to determine the risk coefficient of each factor.α=0.05Results1Expression of P53in low grade and high grade ovarian serous tumor.In20cases of low grade ovarian serous adenocarcinoma and41cases ofhigh grade ovarian serous adenocarcinoma,the positive expression rates were30%and73.2%,the statistical analysis showed that the expression of P53inhigh grade was significantly higher than low grade group,the difference wasstatistically significant (P<0.05)．2Expression of BRMS1, RIZ1and SATB1in low-grade ovarian seroustumor2.1BRMS1protein immunohistochemical resultsIn normal ovarian tissue,benign tumors,borderline serous cystadenomaand low grade ovarian serous adenocarcinoma,the positive expression rates ofBRMS1protein were93.3%,77.1%,55.6%and30%.The positive expressionrate decreased gradually,the differences were statistically significant(P<0.05).2.2RIZ1protein immunohistochemical resultsIn normal ovarian tissue,benign tumors,borderline serous cystadenomaand low grade ovarian serous adenocarcinoma,the positive expression rates ofRIZ1protein were86.7%,81.2%,50.0%and35.0%.The positive expressionrate decreased gradually,the differences were statistically significant(P<0.05).2.3SATB1protein immunohistochemical resultsIn normal ovarian tissue,benign tumors,borderline serous cystadenomaand low grade ovarian serous adenocarcinoma,the positive expression rates ofSATB1protein were0%,35.4%,55.6%and75.0%,the positive expression raterose gradually,the differences were statistically significant (P<0.05). 3Expression of BRMS1,RIZ1and SATB1in high-grade ovarian seroustumor3.1BRMS1protein immunohistochemical resultsIn10cases of normal fallopian tube tissues and41cases of high-gradeovarian serous carcinoma,the positive rates were80%and43.9%.Statisticalanalysis showed that the expression of BRMS1protein in high-grade ovarianserous adenocarcinoma group was significantly lower than normal fallopiantube group,the difference was statistically significant (P<0.05).3.2RIZ1protein immunohistochemical resultsIn10cases of normal fallopian tube tissues and41cases of high-gradeovarian serous adenocarcinoma,the positive rates of RIZ1protein expressionwere80%and43.9%.The expression of of RIZ1protein in high-grade groupwas lower than normal fallopian tube group,the difference was statisticallysignificant (P<0.05).3.3SATB1protein immunohistochemical resultsIn10cases of normal fallopian tube tissues and41cases of high-gradeovarian serous adenocarcinoma, the positive rates of SATB1proteinexpression were10.0%and51.2%.Statistical analysis showed that theexpression of high-grade ovarian serous carcinoma group of SATB1proteinwas significantly lower than the normal fallopian tube group,the differencewas statistically significant (P<0.05).4Expression of genes BRMS1, RIZ1and SATB1in low grade and highgrade ovarian serous adenocarcinoma4.1The expression of BRMS1in low grade and high gradeThe positive rate of BRMS1protein expression in low grade and highgrade ovarian serous adenocarcinoma were30%and43.9%,statistical analysisshowed there was no significant difference (P>0.05).4.2The expression of gene RIZ1in low grade and high gradeThe positive rate of RIZ1protein expression in low grade and high gradeovarian serous adenocarcinoma were35.0%and46.3%,statistical analysisshowed there was no significant difference (P>0.05).4.3The expression of SATB1in low grade and high grade ovarian serouscarcinoma The positive rates of SATB1protein expression in low grade and highgrade were75.0%and51.2%, statistical analysis showed there was nosignificant difference (P>0.05).5The relationship of the expression of P53,BRMS1,SATB1and RIZ1protein and the prognosis in low grade and high grade ovarian serousadenocarcinoma.5.1The comparison of survival rate in low grade and high gradeThe3years and5years survival rates of low grade were85%and70%,however, the3years and5years survival rates of the high grade groupwere34.1%and12.2%,the statistical analysis showed that,the3year and5year survival rates of the two types of serous carcinoma were different (P<0.05).5.2The relationship of P53protein and the prognosis in low grade and highgrade ovarian serous adenocarcinomaIn low grade, the3years and5years survival rates of P53proteinpositive group and negative group showed no significant difference (P>0.05).In high grade,the3years and5years survival rates in P53proteinnegative group were higher than the positive group,the difference wasstatistically significant (P <0.05).5.3The relationship of BRMS1protein and the prognosis in low grade andhigh grade ovarian serous adenocarcinomaIn low grade,the3years and5years survival rates of BRMS1proteinpositive group and negative group showed no significant difference (P>0.05).In high grade,the3years and5years survival rates of in BRMS1protein positive group were higher than that of the negative group,thedifference was statistically significant (P <0.05).5.4The relationship of RIZ1protein and the prognosis in low grade andhigh grade ovarian serous adenocarcinomaIn low grade,the3years and5years survival rates of RIZ1proteinpositive group and negative group showed no significant difference (P>0.05).In high grade,the3years and5years survival rates of RIZ1protein positive group were higher than that of the negative group,the difference wasstatistically significant (P <0.05).5.5The relationship of SATB1protein and the prognosis in low grade andhigh grade ovarian serous adenocarcinomaIn low grade,the3years and5years survival rates of SATB1proteinpositive group and negative group showed no significant difference (P>0.05).In high grade,the3years and5years survival rates of RIZ1proteinpositive group were lower than that of the negative group,the difference wasstatistically significant (P <0.05).6The relationship of different clinical stages and the prognosis in low gradeand high grade ovarian serous adenocarcinoma.In low grade,the3and5years survival rate of different clinical stagesshowed no significant difference (P>0.05).In high grade,the3years and5years survival rates of the early clinical staging group（Stage I,II）were higherthan the late clinical stage group（stage III,IV）, the difference was statisticallysignificant (P <0.05).7The relationship of different mode of chemotherapy and the prognosis inlow grade and high grade ovarian serous adenocarcinoma.In low grade, the3years and5years survival rates of the nopostoperative chemotherapy group, no regular chemotherapy group andregular chemotherapy group had no obvious statistical difference (P>0.05).In high grade, the3years and5years survival rates of the no postoperativechemotherapy group, no regular chemotherapy group and regularchemotherapy group were different, the difference was statistically significant(P <0.05).8The Cox multivariate survival analysis of low grade and high gradeovarian serous adenocarcinomaIn low grade, there were no factors came into the Cox proportionalhazard regression model. In high grade，clinical staging and postoperativechemotherapy came into the Cox proportional hazard regression model． Conclusions:1Compared with high grade and low grade ovarian serousadenocarcinoma，the positive rate of P53protein expression of high gradeovarian serous adenocarcinoma was higher than the low grade group, theresult supported the dualism theory the pathogenesis of ovarian serouscarcinoma, and it also proved that there was a close relationship between theoccurrence of high grade ovarian serous carcinoma and the mutation of geneP53．2In normal ovarian tissue, benign tumors,borderline serous cystadenomaand low grade ovarian serous adenocarcinoma, the positive rate of BRMS1and RIZ1protein expression decreased gradually,however, the positive rate ofSATB1protein expression rose gradually，we could see that these three genesinvolved in the course of from normal ovarian tissues, serous cystadenoma,borderline cystadenoma, low grade ovarian serous adenocarcinoma．3The positive expression rates of BRMS1and RIZ1protein in high gradeovarian serous adenocarcinoma were lower than the normal fallopian tubetissues，the positive rate of SATB1protein in high grade ovarian serousadenocarcinoma was higher than the normal fallopian tube,we could see thatBRMS1, RIZ1and SATB1participated in the occurrence of high gradeovarian serous carcinoma.4There were no differences between the low grade and high gradeovarian serous adenocarcinoma in the positive expression rates of BRMS1,RIZ1and SATB1，so we could see that there still existed many commonmolecular basis in low grade and high grade ovarian serous carcinoma．5There were significant difference in high grade and low grade ovarianserous adenocarcinoma of the3and5years survival rates, the survival rate oflow grade group was obviously higher than high gradegroup.Moreover,BRMS1, RIZ1and SATB1protein expression had norelation with the survival rate of low grade ovarian serousadenocarcinoma,but it had clear relationship with high grade group． 6In low grade, there were no factors came into the Cox proportionalhazard regression model. In high grade,clinical staging and postoperativechemotherapy came into the Cox proportional hazard regression model．... |
PDF Full Text Request