A large number of prostate cancer (PCa) patients receive treatment without significant benefits, strengthening the need for accurate prognosis, which can be supported by the study of miRNAs. In silico specificity analysis was performed for the identification of miRNAs able to regulate KLK2 and KLK4 expression. Total RNA was extracted from prostate tissues obtained from PCa and benign prostate hyperplasia patients. Thereafter, RNA was polyadenylated and reverse transcribed to cDNA, which was used for qPCR analysis. miR-378 was predicted to target both KLK2 and KLK4 and downregulated levels detected in PCa patients (p=0.050). The reduction of miR-378 was correlated with higher Gleason score (p=0.018), larger diameter tumors (p=0.034), and elevated serum PSA (p=0.006). Regarding prognosis, miR-378 was able to improve risk stratification according to Gleason score or tumor stage, while higher risk to recur highlighted for the patients expressing lower miR-378 levels. Finally, the loss of miR-378 was able to predict the short-term relapse of 'high'- and 'very high'-recurrence-risk patients, independent of Gleason score, tumor stage, PSA, and age as indicated by Kaplan-Meier survival curves (p=0.030) and multivariate Cox regression analysis (p=0.018). In conclusion, loss of miR-378 expression increases the risk for PCa progression and relapse, despite active treatment.

OBJECTIVES: More than half of the diagnosed patients with bladder cancer (BCa) recur at least once following their initial treatment. Thus, patients' monitoring and prognosis is of utmost importance. However, the need for intensive surveillance of BCa significantly burdens patients' health-related quality of life. The aim of the present study is the expression analysis of BCL2L12, a recently identified member of the BCL2 apoptosis-related gene family, in BCa and the evaluation of BCL2L12 prognostic significance for the survival outcome of the patients. METHODS AND MATERIALS: Our study included 115 patients with BCa, and tissue specimens were obtained from the tumor area as well as from adjacent normal bladder wall. BCL2L12 expression was determined using quantitative real-time polymerase chain reaction assay, and was further correlated with patients' clinicopathological features and follow-up survival data. RESULTS: Up-regulated BCL2L12 expression levels were detected in malignant bladder specimens compared with normal ones. The higher BCL2L12 expression was further associated with shorter disease-free survival of the patients with BCa. Focusing on patients with TaT1 non-muscle invasive BCa, BCL2L12 expression levels were correlated with higher recurrence rate at the first follow-up cystoscopy and were unveiled to be an independent unfavorable predictor of patients' short-term recurrence following transurethral resection. Finally, BCL2L12 expression levels were also associated with poor disease-free survival of the high-grade TaT1 patients. CONCLUSIONS: Our data highlight the unfavorable prognostic value of BCL2L12 for patients with BCa and support its potential clinical use for the assessment of TaT1 patients' recurrence risk.

INTRODUCTION: Novel therapeutic compounds are needed for prostate cancer (CaP), given the limitations of already used drugs and the disease's mortality, often attributed to castrate resistance. Tissue kallikrein and kallikrein-related peptidases (KLKs) form a family of serine proteases aberrantly expressed and broadly implicated in human malignancies. In CaP, KLKs participate in the promotion of cell proliferation, extracellular matrix degradation, tumour cell invasion and metastasis. AREAS COVERED: This review discusses the different ways of inhibiting, modulating and exploiting KLK activity and/or expression as emerging CaP therapeutics. KLKs are targeted by diverse naturally occurring substances, including proteinaceous inhibitors, low-molecular-weight peptides and Zn(2+). Synthetic KLK inhibitors include protein/peptide-based inhibitors and small molecules. A re-engineered serpin-based KLK inhibitor is under evaluation in first-in-human trials as a CaP therapeutic, whereas additional potent and selective KLK inhibitors with relevance to CaP have been synthesized. KLK3-activated pro-drugs have entered Phase I and Phase II clinical trials as therapeutics for prostate tumours. The KLK3-based PROSTVAC(R) vaccine is evaluated in Phase III clinical trials. Targeting KLK expression via RNA interference methods could represent another promising therapeutic approach for CaP. EXPERT OPINION: Apart from their immense biomarker potential, KLKs also hold promise as the basis of novel CaP therapeutics.

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.