The Relationship Between The Expression Of MMP-3and The Clinicopathological Features And Prognosis Of Bladder Transitional Cell Carcinoma

Objective: Bladder cancer is the most common malignant tumor of theurinary system in China, and its incidence is ranked eighth compared withother kinds of malignant tumor.75%to85%of new bladder cancer cases arenon-muscle invasive bladder cancer,but there is a high proportion ofinfiltration and recurrence within5years.Even after surgery and bladderirrigation, most patients still die of recurrence or metastasis.Tumor invasionand metastasis involve cell movement, cell adhesion, degradation of ECM andangiogenesis.Matric metalloproteinase（MMP） can degrade the extracellularmatrix and basement membrane,correlated with tumor invasion,metastasis andangiogenesis, in which MMP plays an important role.As an important memberof MMP family,MMP-3expression can be detected in many kinds of tumor,which has great significance for tumor invasive behavior and prognosis.In thisstudy, we evaluated MMP-3expression in specimens withimmunohistochemistry and investigated associations of MMP-3expressionwith clinicopathological featuresand prognosis.Methods: Our study included70specimens of bladder transitional cellcarcinomas derived from70patients who underwent either TUR-B orcystectomy in Urology Department of Third Hospital of Hebei MedicalUniversity from July2000to July2006.There were53males and17females,whose ages varied from32to85years, and the median age was64years.According to WHO criteria: G₁26cases, G₂28cases, G₃16cases. Accordingto UICC-TNM stage: T_a,144cases, T₂11cases, T₃9cases and T₄6cases.20normal controls were selected from non-bladder cancer surgery. MMP-3expression of specimens were detectd with immunohistochemistry（SPtwo-step method）. We analyzed experimental data and fllow-up data with correlation analysis, multivariate analysis and survival analysis using SPSS13.0software. There was statistically significant difference when p<0.05inthe test.Results:1The results of immunohistochemistry showed that the expression ofMMP-3protein was primarily expressed in cancer cell cytoplasm and thenucleus, and weak expression in the cancer tissue stroma can be detected inthe specimens from invasive cancer. The positive rates of MMP-3expressionwere52.8%（37/70） and0.0%（0/20） in bladder cancer and normal bladdermucosa respectively, and there was significant difference between the twogroups （p <0.001）.2The positive rate of MMP-3expression of bladder cancer in male groupand female group were49.1%（26/53） and64.7%（11/17） respectively, andthere was no significant difference between the two groups （p>0.05）.3In bladder cancer tissues of old age group （≥65years） and younger agegroup （<65years）, the positive rates of MMP-3were53.5%（23/43） and51.9%（14/27） respectively,and there was no significant difference betweenthe two groups （p>0.05）.4The positive rate of MMP-3expression of bladder cancer in the groupof G₁, G₂and G₃were26.9%（7/26）,60.7%（17/28） and81.3%（13/16）respectively, and there was significantly difference among the three groups （p<0.05）. By pairwise comparison, there was significantly difference betweenG₁and G₂（p <0.05）, and there was significantly difference between G₁and G₃（p <0.05）.But there was no significantly difference between the G₂and G₃group （p>0.05）.5In noninvasive bladder cancer and invasive bladder cancer tissues thepositive rate of MMP-3expression were36.4%（16/44） and77.8%（21/27）respectively,and there was significant difference （p<0.001）.6The positive rate of MMP-3expressions of bladder cancer having a diameterlarger than3cm was77.8%（21/27）, and that of bladder cancer have adiameter less than3cm was37.2%（16/43）,and there was significant difference between the two groups（p <0.01）.7The positive rate of MMP-3expression in the group of single bladdercancer and the multiple bladder cancer, were36.4%（16/44） and77.8%（21/27）respectively, and there was significant difference between the two groups （p<0.05）.8The positive rate of MMP-3expression of recurrence-present bladdercancer was71.4%（15/21）and that of cancer of recurrence-absent was44.9%（22/49）. There was statistically significance difference between the twogroups （p <0.05）.9According to the Spearman rank correlation analysis, there was apositive correlation between MMP-3expression in tumor tissue and anyone ofthese factors,which were pathological grade, pathological stage, tumorsize,tumor number and recurrence of bladder cancer （p<0.05,r>0） whereasthere was no correlation between MMP-3expression in tumor tissue andgender or age （p>0.05）.10Multivariate analysis showed that tumor pathological grading [Exp（B）=2.123, p=0.013], pathological stage [Exp （B）=2.225, p=0.026], tumornumber [Exp （B）=2.064,p=0.010], relapse [Exp （B）=1.732, p=0.031] andcancer tissue expression of MMP-3[Exp （B）=3.255, p=0.003].Each of thesefactors was an independent prognostic factor of bladder cancer （p <0.05）.11According to overall comparison between the level of the survivalcurves of MMP-3positive/negative expression,there was statisticallysignificant difference （P=0.026）.The estimated values of the average survivaltime （Mean） of negative expression group and positive expression group were52.445and42.275respectively, and the estimated values of standard errorwere3.058and3.402respectively,whereas estimated values of the mediansurvival time （Median） of negative expression group and positive expressiongroup were52.445and42.275respectively,and the estimated values ofstandard error were4.898and7.305respectively （month as time unit） in theMMP-3expression group and the negative group.1-year,3-year and5-yearcumulative survival rates of MMP-3negative expression group were93.6%, 84.2%and72.0%respectively, and in positive expression group，1-year,3-year and5-year cumulative survival rates of MMP-3positive expressiongroup were84.0%,66.1%and32.7%respectively.Conclusion:1The immunohistochemical results show the MMP-3protein isprimarily expressed in cytoplasm and the nucleus of tumor cell, and there isweak MMP-3expression in interstitial of invasive bladder cancer. Thepositive expression of MMP-3in bladder cancer group is significantly higherthan that in normal bladder mucosa group,which suggests that the MMP-3may be involved in migration and invasion of tumor cell,promoting thedevelopment of bladder cancer.2The positive rate of MMP-3expression is significantly increased inbladder cancer with higher grade or stage, larger diameter, greater number orrecurrence.MMP-3expression shows no significant difference either in agegroups or in gender groups. MMP-3expression of tumor tissues is positivelycorrelated with stage,grade, size, number and recurrence of tumor,whereasthere is no correlation between MMP-3expression in tumor tissue and genderor age. Higher MMP-3expression of bladder cancer may enhance invasionability of tumor cell, which promotes growth, invasion and recurrence ofbladder cancer3Pathological grade, pathological stage,tumor number,recurrence andexpression of the MMP-3are all independent prognostic factors of bladdercancer. Each of them affects the survival time of the patients with bladdercancer. Bladder cancer with higher grade or stage, larger diameter, greaternumber or recurrence may indicate a poor prognosis and higher death risk ofthe patient.4The overall survival, median survival time and cumulative survivalrates of MMP-3expression positive group were significantly lower than thoseof MMP-3expression negative group,which incidates that detecting MMP-3expression in bladder cancer previously may help to predict survive time andsurvival rate,which enables clinical doctors to identify bladder cancer patients with high-risk of recurrence and metastasis at early stage,who could benefitfrom the optimal individualized treatment options, close fllow-up andintervention.Downregulation of MMP-3expression and activity may beeffective ways to inhibit cancer development or cure cancer.