This study aimed to investigate the microRNA (miRNA) profile in prostate carcinoma tissue by microarray analysis and RT-qPCR, to clarify associations of miRNA expression with clinicopathologic data and to evaluate the potential of miRNAs as diagnostic and prognostic markers. Matched tumor and adjacent normal tissues were obtained from 76 radical prostatectomy specimens. Twenty-four tissue pairs were analyzed using human miRNA microarrays for 470 human miRNAs. Differentially expressed miRNAs were validated by TaqMan RT-qPCR using all 76 tissue pairs. The diagnostic potential of miRNAs was calculated by receiver operating characteristics analyses. The prognostic value was assessed in terms of biochemical recurrence using Kaplan-Meier and Cox regression analyses. Fifteen differentially expressed miRNAs were identified with concordant fold-changes by microarray and RT-qPCR analyses. Ten microRNAs (hsa-miR-16, hsa-miR-31, hsa-miR-125b, hsamiR-145, hsa-miR-149, hsa-miR-181b, hsa-miR-184, hsa-miR-205, hsa-miR-221, hsa-miR-222) were downregulated and 5 miRNAs (hsa-miR-96, hsa-miR-182, hsa-miR-182*, hsa-miR-183, hsa-375) were upregulated. Expression of 5 miRNAs correlated with Gleason score or pathological tumor stage. Already 2 microRNAs classified up to 84% of malignant and nonmalignant samples correctly. Expression of hsa-miR-96 was associated with cancer recurrence after radical prostatectomy and that prognostic information was confirmed by an independent tumor sample set from 79 patients. That was shown with hsa-miR-96 and the Gleason score as final variables in the Cox models build in the 2 patient sets investigated. Thus, differential miRNAs in prostate cancer are useful diagnostic and prognostic indicators. This study provides a solid basis for further functional analyses of miRNAs in prostate cancer.

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Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n ‫؍‬ 39; pN1M0, n ‫؍‬ 34; M1, n ‫؍‬ 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin ( Key words: bone turnover marker; prostate carcinoma; bone metastasis; osteoprotegerin; diagnostic accuracyThe most frequent cancer in men, PCa, is characterized by the occurrence of skeletal metastases in about 65-75% of patients with advanced disease. 1 Bone metastases alter the balance between bone formation and bone resorption by influencing the involved bone cells (osteoblasts and osteoclasts) through local release of cytokines and growth factors. To detect and monitor this metastatic bone involvement, bone scintigraphy is the widely applied standard method. Altered bone remodeling activity can also be assessed either directly by measuring components of the affected bone cells (osteoblasts and osteoclasts) or indirectly by analyzing metabolic products released from the bone matrix following the changed bone formation or resorption. Bone turnover markers that reflect either bone formation in consequence of osteoblast proliferation or analytes indicating bone resorption as the opposite bone remodeling activity have been recommended as tools in the assessment of bone metastasis in PCa. [2][3][4][5][6][7] The balance between osteoblastic and osteoclastic activity in bone is essentially determined by osteoclastogenesis, which is regulated by 3 proteins: RANK, RANKL and OPG. OPG and RANKL could be, in addition to bone formation and resorption markers, biomarkers to detect bone metastases. 8,9 It was therefore interesting that these 2 proteins were overexpressed in bone metastases of PCa patients. 10,11 Several studies have assessed the diagnostic efficacy of both bone formation and resorption markers for the detection of bone metastases in PCa. 6 However, they often included only a few bone markers or a limited number of patients. 7,12 While little comparative data are available on the diagnostic accuracy of the newly developed assays for the various analytes including OPG and RANKL, the conclusions regarding the diagnostic usefulness need to be reconsidered. 9,13 In addition, the recommendation of diagnostic tests was often substantiated by the univariate evaluation of data without taking into account the usefulness of multivariate analysis. Therefore, our aims were (i) to measure serum markers of bone formation, bone resorption and osteoclastogenesis as noninvasive, easy-to-determine analytes of bone metastases in the same serum samples; (ii) to evaluate and compare the diagnostic validity of all analytes concerning their differential efficiency between patients with and without metastases; (iii) to recom...

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The majority of prostate cancers harbor recurrent gene fusions between the hormone-regulated TMPRSS2 and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERG rearrangements represent a distinct subclass of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and gene expression signatures. The current study describes the frequency of ERG rearrangement prostate cancer and three 5 prime (5') gene fusion partners (i.e., TMPRSS2, SLC45A3 and NDRG1) in a large prostatectomy cohort.ERG gene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3, and NDRG1 were assessed using fluorescence in-situ hybridization (FISH) on prostate cancer samples from 614 patients treated by radical prostatectomy. ERG rearrangement occurred in 53% of the 540 assessable cases. TMPRSS2 and SLC45A3 were the only 5' partner in 78% and 6% of these ERG rearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases demonstrated concurrent TMPRSS2 and SLC45A3 rearrangements. TMPRSS2 or SLC45A3 rearrangements could not be identified for 5% of the ERG rearranged cases. From these remaining cases we identified one case with NDRG1 rearrangement. We did not observe any associations with pathologic parameters or clinical outcome.This is the first study to describe the frequency of SLC45A3-ERG fusions in a large clinical cohort. Most studies have assumed that all ERG rearrangement prostate cancers harbor TMPRSS2-ERG fusions. This is also the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearrangement prostate cancer. Incorporation of these less common ERG rearrangement prostate cancer fusion assays could further increase the sensitivity of these PCR-based approaches.

GOLPH2 is coding the 73-kDa type II Golgi membrane antigen GOLPH2/GP73. Upregulation of GOLPH2 mRNA has been recently reported in expression array analyses of prostate cancer. As GOLPH2 protein expression in prostate tissues is currently unknown, this study aimed at a comprehensive analysis of GOLPH2 protein in benign and malignant prostate lesions. Immunohistochemically detected GOLPH2 protein expression was compared with the basal cell marker p63 and the prostate cancer marker a-methylacylCoA racemase (AMACR) in 614 radical prostatectomy specimens. GOLPH2 exhibited a perinuclear Golgi-type staining pattern and was preferentially seen in prostatic gland epithelia. Using a semiquantitative staining intensity score, GOLPH2 expression was significantly higher in prostate cancer glands compared with normal glands (Po0.001). GOLPH2 protein was upregulated in 567 of 614 tumours (92.3%) and AMACR in 583 of 614 tumours (95%) (correlation coefficient 0.113, P ¼ 0.005). Importantly, GOLPH2 immunohistochemistry exhibited a lower level of intratumoral heterogeneity (25 vs 45%). Further, GOLPH2 upregulation was detected in 26 of 31 (84%) AMACR-negative prostate cancer cases. These data clearly suggest GOLPH2 as an additional ancillary positive marker for tissue-based diagnosis of prostate cancer.

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Epidemiological studies have consistently associated high intakes of lycopene or vitamin E with a reduced prostate cancer risk. Both compounds were tested in the MatLyLu Dunning prostate cancer model to gain insight into the in vivo action of lycopene and vitamin E. Supplementation for 4 weeks with 200 ppm lycopene, 540 ppm vitamin E, or both led to plasma levels comparable with those in humans. Both compounds also accumulated in tumor tissue. Macroscopic evaluation of the tumors by magnetic resonance imaging showed a significant increase in necrotic area in the vitamin E and the lycopene treatment groups. Microarray analysis of tumor tissues revealed that both compounds regulated local gene expression. Vitamin E reduced androgen signaling without affecting androgen metabolism. Lycopene interfered with local testosterone activation by down-regulating 5-alpha-reductase and consequently reduced steroid target genes expression (cystatin-related protein 1 and 2, prostatic spermine binding protein, prostatic steroid binding protein C1, C2 and C3 chain, probasin). In addition, lycopene down-regulated prostatic IGF-I and IL-6 expression. Based on these findings, we suggest that lycopene and vitamin E contribute to the reduction of prostate cancer by interfering with internal autocrine or paracrine loops of sex steroid hormone and growth factor activation/synthesis and signaling in the prostate.