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Paper text:
prostate cancer ( pca ) is one of the most commonly diagnosed male malignancies ; some of them are slow growing , whereas others are more aggressive .
men who have a brother or father with pca have twice the risk of developing pca .
cancer cells may metastasize from the prostate to other parts of the body , particularly the bones and lymph nodes .
moreover , there is a significant number of men who require systemic therapy and ongoing surveillance for advanced pca .
therefore , genetic studies of this disease and new therapeutic strategies are urgently needed for the prevention and the treatment of pca .
apoptosis is a programmed cell death process that takes place under normal physiological and pathological conditions .
inhibition of apoptosis is a critical pathophysiological factor that contributes to the onset and progression of pca , but the molecular mechanisms are not entirely understood .
therefore , insight into the mechanism(s ) of an abnormal apoptosis regulation may be the basis for developing more effective therapeutic approaches to destroy apoptosis - resistant tumor cells , as those found in pca .
poly ( adp - ribose ) polymerase 1 ( parp-1 ) gene is located to 1q42 ; it is 43 kb long and is split into 23 exons ( omim 173870 ) .
parp-1 is a chromatin associated enzyme that participates to cell cycle regulation , transcription , tumorigenesis , and cellular response to dna damage .
parp-1 has an important roles in dna base excision repair ( ber ) , acting as a nick sensor , and modulator of key dna repair molecules . upon activation
, parp-1 synthesizes poly ( adp - ribose ) ( par ) using nicotinamide adenine dinucleotide ( nad+ ) as a substrate and covalently transfers par to nuclear proteins , including nucleosomal core histones , topoisomerases i and ii , high mobility group ( hmg ) proteins , and p53 .
genetic and pharmacological studies have shown that parp-1 overexpression is a key mediator of programmed - necrotic cell death in vivo .
furthermore , parp1 is required for translocation of the apoptosis - inducing factor ( aif ) from the mitochondria to the nucleus and it is proteolytically cleaved at the onset of apoptosis by casp3 . 
 parp-1 appears to be also involved in programmed cell death processes , such as apoptosis or macroautophagocytotic cell death .
analysis of parp-1 gene expression showed that parp-1 is highly expressed in several types of tumors including prostate cancer , colorectal cancer , pancreatic cancer , hepatocellular carcinoma , cutaneous malignant melanomas , and glioblastoma multi - forme .. the present study was undertaken to evaluate the expression of parp-1 protein by immunohistochemistry in normal prostate tissues and in prostate cancer according to their gleason score .
the gleason score system , in addition to other parameters , is used to evaluate the prognosis of men with prostate cancer and to guide the treatment .
the study included 40 cases of pca with different gleason score , and 37 cases of normal prostatic tissues ( 6 prostates removed by post mortem autopsy in normal donors and 31 prostatic biopsies ) .
the diagnosis and grading of pca was made according to the 2005 international society of urological pathology ( isup ) consensus conference , by two different pathologists ( ag and ff ) .
the protocol was approved by the internal institutional review board and an informed written consent was obtained from each patient with pca or , if deceased , by his / her relatives . prostate section ( 4 m thick )
parp-(f-2 ) , a mouse monoclonal antibody raised against human parp-1 protein , was used for immunohistochemistry ( santa cruz biotechnology , inc .
, heidelberg , germany ) . as indicated by the manufacturer instructions , this antibody , at the dilution of 1:300 , has been shown to reliably recognize parp-1 proteins in pca and normal prostate by immunohistochemistry .
slides were deparaffinized , rehydrated , subjected to three 5 min cycles in a microwave at 360 w in citrate buffer , preincubated in 3% h2o2 in citrate buffer , and thoroughly washed in 50 mm tris - cl ( ph 7.4 ) , 150 mm nacl tris buffered saline ( tbs ) containing 0.05% tween 20 ( washing buffer ) .
slides were then pre - incubated with 3% bovine serum albumin ( bsa ) in tbs for 30 min , incubated with 1:300 dilution of anti - parp-1 antibody in tbs containing 1% bsa , thoroughly washed in washing buffer before detection with the lsab 2 kit ( anti mouse , biotinylated and peroxidase - labeled streptavidin ) and 3,3-diaminobenzidine-4hcl ( dab ; dako , carpinteria , ca , usa ) following the instructions contained in the kit .
after detection , the sections were counterstained with haematoxylin , dehydrated and mounted in xylen - based dpx mountant ( bdh , pool , uk ) .
slides were observed and cells visually scored at 10x , 20x , and 40x . to evaluate the percentage of positive tumor cells ,
parp-1 positive cells were evaluated independently in a blinded fashion by two observers ( ga and sm ) . no significant difference was observed between the two observers .
data were analyzed by student s t - test or 1-way analysis of variance ( anova ) followed by the duncan s multiple range test .
the study included 40 cases of pca with different gleason score , and 37 cases of normal prostatic tissues ( 6 prostates removed by post mortem autopsy in normal donors and 31 prostatic biopsies ) .
the diagnosis and grading of pca was made according to the 2005 international society of urological pathology ( isup ) consensus conference , by two different pathologists ( ag and ff ) .
the protocol was approved by the internal institutional review board and an informed written consent was obtained from each patient with pca or , if deceased , by his / her relatives .
prostate section ( 4 m thick ) were obtained from all normal donors and pca patients .
parp-(f-2 ) , a mouse monoclonal antibody raised against human parp-1 protein , was used for immunohistochemistry ( santa cruz biotechnology , inc . , heidelberg , germany ) .
as indicated by the manufacturer instructions , this antibody , at the dilution of 1:300 , has been shown to reliably recognize parp-1 proteins in pca and normal prostate by immunohistochemistry .
slides were deparaffinized , rehydrated , subjected to three 5 min cycles in a microwave at 360 w in citrate buffer , preincubated in 3% h2o2 in citrate buffer , and thoroughly washed in 50 mm tris - cl ( ph 7.4 ) , 150 mm nacl tris buffered saline ( tbs ) containing 0.05% tween 20 ( washing buffer ) .
slides were then pre - incubated with 3% bovine serum albumin ( bsa ) in tbs for 30 min , incubated with 1:300 dilution of anti - parp-1 antibody in tbs containing 1% bsa , thoroughly washed in washing buffer before detection with the lsab 2 kit ( anti mouse , biotinylated and peroxidase - labeled streptavidin ) and 3,3-diaminobenzidine-4hcl ( dab ; dako , carpinteria , ca , usa ) following the instructions contained in the kit . after detection
, the sections were counterstained with haematoxylin , dehydrated and mounted in xylen - based dpx mountant ( bdh , pool , uk ) .
slides were observed and cells visually scored at 10x , 20x , and 40x . to evaluate the percentage of positive tumor cells ,
parp-1 positive cells were evaluated independently in a blinded fashion by two observers ( ga and sm ) .
data were analyzed by student s t - test or 1-way analysis of variance ( anova ) followed by the duncan s multiple range test .
patients with prostate carcinoma had a mean of 69.38.0 years , which did not differ significantly from controls ( 73.09.0 years ) .
immunohistochemical analysis of paraffinembedded sections revealed a strong nuclear signals for parp-1 staining in both normal and prostate carcinoma cells .
no cytoplasmic staining was observed in any sample of both groups ( figure 1 ; figure 2a , b ) .
the percentage of parp-1-positive cells resulted significantly higher in patients with prostate carcinoma compared with controls ( p<0.001 , student s t - test ) ( figure 3 ) . according to the gleason score ,
the percentage of cells with positive nuclear parp-1 staining resulted significantly higher than controls compared to that observed in patients with gleason scores of 6 ( 9 cases ) , 7 ( 10 cases ) , 8 ( 16 cases ) or 9 ( 5 cases ) ( p<0.05 , anova followed by duncan test ) ( figure 4 ) .
in addition , the percentage of parp-1-positive nuclei in patients with a gleason score of 8 were significantly higher than that observed in patients with a gleason score of 6 ( p<0.05 , anova followed by duncan test ) ( figure 4 ) .
a significantly higher number in cells expressing parp-1 proteins in pca tissues compared with the normal prostate cells confirmed previous studies showing the association of this gene over - expression with tumors .
the greater expression of parp-1 protein in pca compared to normal prostate may relate to the its close functional / structural relationship with the factors which favors the activation of the proapoptotic mechanisms , suggesting that pro - apoptotic mechanisms may be activated in these tumors .
this may , in part , justify the presence of parp-1 protein in some tumors , such as non - hodgkin s lymphomas , breast , ovarian , lung , endometrial and skin cancers .
parp-1 is an abundant , chromatin - associated enzyme present in all eukaryotic cell nuclei , where it plays an important function in the maintenance of genomic integrity and transcriptional control .
poly(adp - ribose ) polymerase-1 inhibitor , increases the antitumor activity against glioma , intracranial melanoma , lymphoma , and hematological neoplasias .
activation of parp-1 gene in response to dna damage is an important mechanism to maintain the homeostasis or to trigger apoptosis .
the function of parp-1 has been studied in primary human lung cell cultures from normal human bronchial epithelial cells ( nhbec ) and peripheral lung cells ( plc ) from lung cancer patients grown as explant cultures , over a period of 12 weeks .
recent data on parp-1 agree on the meaning of this gene expression in tumors . accordingly , the results of this study indicate that parp-1 gene may play a role in pca . in conclusion ,
parp-1 over - expression in prostate cancer tissues compared with normal prostate cells suggests a greater activity of parp-1 in these tumors .
in addition , parp-1 proteins was expressed in a significantly greater number of cells in sample with a greater gleason score .
these findings lead to hypothesize that parp-1 protein over - expression in pca is an attempt to trigger apoptosis in this type of tumor .
a genetic background has been implicated in the development of prostate cancer . 
 protein microarrays have enabled the identification of proteins , some of which associated with apoptosis , that may play a role in the development of such a tumor . 
 inhibition of apoptosis is a co - factor that contributes to the onset and progression of prostate cancer , though the molecular mechanisms are not entirely understood . 
 poly ( adp - ribose ) polymerase 1 ( parp-1 ) gene is required for translocation of the apoptosis - inducing factor ( aif ) from the mitochondria to the nucleus . 
 hence , it is involved in programmed cell death . 
 different parp-1 gene expression has been observed in various tumors such as glioblastoma , lung , ovarian , endometrial , and skin cancers . 
 we evaluated the expression of parp-1 protein in prostatic cancer and normal prostate tissues by immunohistochemistry in 40 men with prostate cancer and in 37 normal men . 
 positive nuclear parp-1 staining was found in all samples ( normal prostate and prostate cancer tissues ) . 
 no cytoplasmic staining was observed in any sample . 
 parp-1-positive cells resulted significantly higher in patients with prostate carcinoma compared with controls ( p<0.001 ) . parp-1 over - expression in prostate cancer tissue compared with normal prostate suggests a greater activity of parp-1 in these tumors . 
 these findings suggest that parp-1 expression in prostate cancer is an attempt to trigger apoptosis in this type of tumor similarly to what reported in other cancers .