Expression Of PDCD5 In Tissues Of Human Prostate Cancer And Relations Between PDCD5 And Androgen Receptor Expressing

BackgroundAt present,prostate cancer,surpassing lung cancer,has been the most commonly diagnosed in men in USA.China is still belong to one of the PCa low-risk areas,but, with the westernization of dietary pattern and aging population secondary to development of economy,the incidence of PCa has risen dramatically in some economies leading parts of China.Because of poor public comprehension of PCa and Low screening with serum PSA in China,only 6.2%of patients diagnosed with PCa were initially suspected of having the diease based on serum PSA elevations, contrarily,the vast majority of patients were based on finding of voiding symptoms and/or signs and symptoms related to metastatic diease.A study suggested the median value of PSA in chinese patients with PCa was 46.1μg/L,and the 5-year survival rate for patients with PCa in Shanghai was 36.5%from 1988 to 1995.It is thus clear that the epidemiologic characterictics of PCa in China currently is low morbidity,high proportion in later cases and low survival rate.In a multivariate analysis,Gleason grade,serum PSA level,capsular penetration and margines of resection were all strong independent predictors of progression,and Gleason sum is the most reliable one.On the basis of Gleason grade,serum PSA level and clinical staging,PCa is divided into three groups as low-risk,middle-risk and high-risk in 2007 edition Guidelines on Urology of China.The growth of PCa depends on the rate of cells proliferating balanced by the rate of cells dying,apoptosis induced by a series of promoters and inhibitors is one of the crux steps in the process.The factors related to apoptosis include promoters(Caspases family,P53,Fas/FasL,et al) and inhibitors(IAP family,Clusterin,TRPM-2,et al). Bcl-2 and Bcl-XL of Bcl-2 family downregulate apoptosis,but Bax,Bad and Bak upregulate apoptosis.The majority of studies stated inhibitors such as Bcl-2,Survivin,Clusterin and TRPM-2 are higher expressed in PCa tissues than in normal prostate and BPH tissues and the level of inhibitors expression increase with the cancer advancing,but,the promotors such as P53 and Bax show inverse effects,all these indicated apoptosis downregulation make a role in growth of PCa.But some other studies about expression of Bcl-2/Bax and Fas/FasL in PCa tissues getting quite different results demomstated that apoptosis upregulation is associated with growth of PCa,and the apoptosis enhances with Gleason sum increasing.What's more,the conventional view,that expression of androgen receptor(AR) has a negative correlation with differentiation of PCa cells and deletion of AR accompanied with apotosis downregulation induces AIPC/HRPC,is faced with constant challenge.Kinoshita etc. found higher expression of AR in 80%of HRPC comparing to deletion of AR in 20-30%of HRPC,indicating just the increase of quantity and activity and changes of nature in AR following mutation cause HRPC.Diao etc.compared two groups PCa cases as AR(-) and AR(+),the results showed the apoptosis enhanced in AR(-) group than in AR(+) group.The researches above-mentioned documented the definite role of apoptosis in PCa development is still not so clear,and the mechanism about apoptosis regulation of PCa cells may be more complicated beyond expectation.Although controversi es existing,it is certain apoptosis has close correlations with occurrence,development and treatment effects of PCa,exploration in expression and significance of apoptosis-regulating factors in levels from gene to its product may contribute to improvement of diagnosis and treatment of PCa.TFAR19(TF-1 apoptosis-related gene 19) was first reported by Peking University Center for Human Disease Genomics in 1999,then designated PDCD5 (Programmed Cell Death 5) by International Human Gene Nomination Committee with the registration number of AF014955.Several extracorporal tests showed PDCD5 could inhibit the growth of some tumor cells(cervical cancer,ovarian cancer, hepatocellular cancer,etc.) by upregulating apoptosis and cooperate with radiotherapy and chemotherapy.In recent years,we introduced PDCD5 into study about mechanism of urologic tumors.With immunohistochemistry technique,we detected the expression of PDCD5 in tissues of normal human kidney and renal clear cell carcinoma,the results showed PDCD5 expressed stronger in renal tubule of normal kidney than in renal clear cell carcinoma,the expression of PDCD5 was downregulated along the progression of renal cell carcinoma,which suggested PDCD5 is an important apoptosis regulating factor in the occurrence and development of renal clear cell carcinoma.So far,studies about PDCD5 almost were limited in laborarotic stage,and no data related to expression of PDCD5 in tissues of normal human prostate,BPH and prostate cancer has been reported.ObjectivesThe aim of present research is to investigate the expression of PDCD5 in tissues of normal human prostate,BPH and prostate cancer,and explore the relationship between PDCD5 and AR expressing in PCa tissues.By this way,the possible role PDCD5 making in occurrence and development of PCa by inducing apoptosis may be demonstrated,and the clinical value of PDCD5 being a new predictors of progression and target of gene therapy of PCa could be assessed.Materials and Methods22 PCa samples were selected from patients recently taking radical prostatectomy(no radiotherapy,chemotherapy or endocrine treatment were taken before operations).On the basis of Gleason grade,all the samples were divided into three groups as low-risk(Gleason sum≤6),middle-risk(Gleason sum=7) and high-risk(Gleason sum≥8).22 BPH samples were selected from patients taking suprapubic prostatectomy and TURP from 2007.1 to 2007.9,with a mean age of 69.7 years old(range 61-78 years old).12 normal prostate samples with a mean age of 28.3 years old(range 21-36 years old) were selected as control groups.The expressions of PDCD5 were tested by EnVision immunohistochemical methods in all samples,normal cervix tissues were used as positive contrast and PBS replacing the first antibody as negative contrast.Positive expression rates and intensity of PDCD5 protein were investigated by observing under microscope and analyzing with computer imaging technique.Positive expression rates and intensity of PDCD5 protein were investigated by observing under microscope and analyzing with computer imaging technique.Also by the mean of EnVision method,using BPH tissues used as positive contrast and PBS replacing the first antibody as negative contrast,22 PCa samples were divided into AR(+) and AR(-) group,the expression of PDCD5 was compared between two groups.All statistical analyses were carried out with SPSS10.0 software. Independent-Samples T Test and one-Way ANOVA were used for the measurement data.Rank sum test or Chi-square test was used for the count data respectively. Probability below 0.05 was considered statistically significant.Results1.The expression of PDCD5 immunohistochemical staining in tissues of normal prostate,BPH and prostate cancer in different pathologic stagesThe main staining site of PDCD5 is located in cytoplasm but partly in cytonucleus.The 3 middle-risk PCa samples were merged With low-risk PCa samples as low/middle-risk PCa group compared with high-risk PCa group,normal prostate group and BPH group.The statistical outcomes showed,there was no significant difference between the expression of PDCD5 in normal prostate and BPH tissues (p=1.000).Low/middle-risk PCa and high-risk PCa group comparing with normal prostate and BPH group indicated obvious statistical significance(Low/middle-risk vs normal prostate,p=0.001;Low/middle-risk vs BPH,p=0.001;high-risk vs normal prostate,p=0.000;high-risk vs BPH,p=0.000),what's more,the expression of PDCD5 in Low/middle-risk and high-risk has obvious differences(p=0.019). The statistical outcomes above-mentioned indicated PDCD5 expressed obvious lower in PCa than in BPH and normal prostate tissues,the expression of PDCD5 was downregulated further with the increase of Gleason sum.2.The image analyses of immunohistochemical staining of PDCD5 in tissues of normal prostate,BPH and prostate cancer in different pathologic stagesThere was no significant difference between the intensity of IH staining of PDCD5 in normal prostate and BPH tissues(p=0.290).Low/middle-risk PCa and high-risk PCa group comparing with normal prostate and BPH group indicated obvious statistical significance(Low/middle-risk vs normal prostate,p=0.000;Low/ middle-risk vs BPH,p=0.001;high-risk vs normal prostate,p=0.000;high-risk vs BPH,p=0.000),and the intensity of IH staining of PDCD5 in Low/middle-risk and high-risk has obvious differences(p=0.014).The statistical outcomes of quantitative analysis were highly identical to that of qualitative analysis,further indicated the downregulation of PDCD5 being related to the occurrence and development of PCa.3.PDCD5 detection in PCa AR(+)/AR(-) groupThe staining site of AR is located in cytonucleus.13 samples were AR(+) and 9 samples were AR(-) among all 22 PCa samples.PDCD5 expression in PCa tissues between AR(+) and AR(-) group were analysed,the exact value of Probability 0.060,which indicated no statistically difference between the two groups.4.The image analyses of immunohistochemical staining of PDCD5 in PCa AR(+)/AR(-) groupDifferent with the qualitative analysis,the statistical outcome of the quantitative analysis showed the intensity of IH staining of PDCD5 in AR(+) was obviously higher than AR(-) group(p=0.006).5.The expression of AR immunohistochemical staining in tissues of prostate cancer in different pathologic stagesThe statistical outcomes indicated there was no significant difference between the expression of PDCD5 in Low/middle-risk PCa and high-risk PCa group(p=1.000 by McNemar test and p=0.187 by Measure of Agreement Kappa)Conclusions1.PDCD5 expresses strongly both in normal prostate and BPH tissues with no difference.2.PDCD5 expresses obvious lower in PCa than in BPH and normal prostate tissues,the expression of PDCD5 was downregulated further with the increase of Gleason sum,which indicates PDCD5 may be an important apoptosis regulating factor in the occurrence and development of PCa.3.The expression of PDCD5 in AR(-)PCa is obvious lower than in AR(+) PCa,which suggests deletion of AR may be accompanied with or induce apotosis downregulation and cause AIPC/HRPC.4.Confirmed by more studies,PDCD5 has a potential clinical value to be new predictors of progression and target of gene therapy of PCa.5.The diversification of PCa cells apoptosis in different individuals existing,the definite role of apoptosis in PCa development is still not so clear,and the studies on different signals pathway of apoptosis regulation in PCa cells may contribute to explore the mechanism of occurance and development of PCa.