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One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPP(Δ8/Δ8) mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression.

Previously, we identified the calcium-activated nucleotidase 1 (CANT1) transcript as up-regulated in prostate cancer. Now, we studied CANT1 protein expression in a large cohort of nearly 1000 prostatic tissue samples including normal tissue, prostatic intraepithelial neoplasia (PIN), primary carcinomas, metastases, and castrate-resistant carcinomas, and further investigated its functional relevance. CANT1 displayed predominantly a Golgi-type immunoreactivity with additional and variable cytoplasmic staining. In comparison to normal tissues, the staining intensity was significantly increased in PIN lesions and cancer. In cancer, high CANT1 levels were associated with a better prognosis, and castrate-resistant carcinomas commonly showed lower CANT1 levels than primary carcinomas. The functional role of CANT1 was investigated using RNA interference in two prostate cancer cell lines with abundant endogenous CANT1 protein. On CANT1 knockdown, a significantly diminished cell number and DNA synthesis rate, a cell cycle arrest in G(1) phase, and a strong decrease of cell transmigration rate and wound healing capacity of CANT1 knockdown cells was found. However, on forced CANT1 overexpression, cell proliferation and migration remained unchanged. In summary, CANT1 is commonly overexpressed in the vast majority of primary prostate carcinomas and in the precursor lesion PIN and may represent a novel prognostic biomarker. Moreover, this is the first study to demonstrate a functional involvement of CANT1 in tumor biology., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

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 alpha-methylacyl-CoA 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 (P<0.001). GOLPH2 protein was upregulated in 567 of 614 tumours (92.3%) and AMACR in 583 of 614 tumours (95%) (correlation coefficient 0.113, P = 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.

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.

Objective: Reliable prognostic tools for prostate cancer are still needed and KLK14, a young member of the growing family of human kallikrein-related peptidases, has been estimated to become a new significant marker. It is the aim of this study to analyze the clinical value of immunohistochemical expression of KLK14 in prostate cancer tissue samples., Methods: Protein expression of KLK14 was assessed immunohistochemically in 186 tissue samples from radical prostatectomies. Areas of normal prostatic tissue, of prostatic epithelial neoplasia and of prostatic adenocarcinoma were checked in relation to clinicopathological parameters of the patients. Expression of KLK14 mRNA was quantified in 25 matches of normal and cancerous prostatic tissue, collected by laser capture microdissection. Real-time reverse transcriptase polymerase chain reaction analysis was used to supplement the immunohistochemical data., Results: Expression of the KLK14 protein correlated with the pathological tumor status in prostate cancer and was associated with disease progression defined by prostate-specific antigen relapse in univariate Kaplan-Meier analysis. The multivariate Cox proportional hazards regression model proved KLK14 to be an independent prognostic factor in prostate cancer., Conclusion: In conclusion, we consider KLK14 to be a suitable prognostic marker for the detection of cases at risk of disease progression after radical prostatectomy., ((c) 2008 S. Karger AG, Basel)

Objectives: Decreased expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) was recently shown in several cancer types. To evaluate its potential role for prostate carcinoma, we investigated RECK expression in prostate cancer (pCA) samples., Methods: RECK messenger RNA levels in 15 microdissected normal/tumor matches were determined by quantitative reverse transcriptase-polymerase chain reaction. Protein expression of RECK was evaluated by immunohistochemical staining in tissue samples of adenomectomies (n=24) and pCA samples after radical prostatectomy (n=247). RECK expression was related to preoperative prostate-specific antigen (PSA), tumor stage and grade, surgical margin status, and PSA relapse-free time after radical prostatectomy., Results: Consistent with lower RECK messenger RNA by 24%, RECK protein expression was decreased in pCA, compared with adjacent normal tissue and prostatic intraepithelial neoplasia. RECK expression in samples of benign prostatic hyperplasia from adenomectomy specimens was higher than in normal adjacent tissue of prostate carcinomas. Decreased RECK expression was associated with higher Gleason score (> or =7) and higher tumor stage. Multivariate analysis using the Cox proportional hazards model revealed that negative RECK expression was an independent prognostic factor for an increased risk of PSA relapse, especially in patients with higher tumor grades (Gleason score > or =7)., Conclusions: Decreased RECK expression correlating with the aggressiveness of pCA and the PSA relapse-free time could become an adjunct tissue biomarker to improve the follow-up and treatment decision for these pCA patients.