The aim of this study was to identify a urine extracellular vesicle circular RNA (circRNA) classifier that could detect high-grade prostate cancer (PCa) of Grade Group (GG) 2 or greater. For this purpose, we used RNA sequencing to identify candidate circRNAs from urinary extracellular vesicles from 11 patients with high-grade PCa and 11 case-matched patients with benign prostatic hyperplasia. Using ddPCR in a training cohort (n = 263), we built a urine extracellular vesicle circRNA classifier (Ccirc, containing circPDLIM5, circSCAF8, circPLXDC2, circSCAMP1, and circCCNT2), which was evaluated in two independent cohorts (n = 497, n = 505). Ccirc showed higher accuracy than two standard of care risk calculators (RCs) (PCPT-RC 2.0 and ERSPC-RC) in both the training cohort and the validation cohorts. In all three cohorts, this novel urine extracellular vesicle circRNA classifier plus RCs was statistically more predictive than RCs alone for predicting ≥ GG2 PCa. This assay, which does not require precollection digital rectal examination nor special handling, is repeatable, noninvasive, and can be easily implemented as part of the basic clinical workflow.

Prostate cancer is the most commonly diagnosed non-cutaneous cancer and one of the leading causes of cancer death for North American men. Whereas localized prostate cancer can be cured, there is currently no cure for metastatic prostate cancer. Here we report a novel approach that utilizes designed chimeric transcription activator-like effectors (dTALEs) to control prostate cancer metastasis. Transfection of dTALEs of DNA methyltransferase or demethylase induced artificial, yet active locus-specific CpG and subsequent histone modifications. These manipulations markedly altered expression of endogenous CRMP4, a metastasis suppressor gene. Remarkably, locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 cells abolished metastasis, whereas locus-specific CpG methylation of the promoter in non-metastatic 22Rv1 cells induced metastasis. CRMP4-mediated metastasis suppression was found to require activation of Akt/Rac1 signaling and down-regulation of MMP-9 expression. This proof-of-concept study with dTALEs for locus-specific epigenomic manipulation validates the selected CpG methylation of CRMP4 gene as an independent biomarker for diagnosis and prognosis of prostate cancer metastasis and opens up a novel avenue for mechanistic research on cancer biology.

Introduction Erectile dysfunction (ED) represents a common quality-of-life issue of any treatment used for prostate cancer, including high-intensity focused ultrasound (HIFU) and targeted cryoablation of the prostate (TCAP). There is a paucity of comparative studies regarding the difference in the erectile function and penile size of patients undergoing HIFU or TCAP. Aim The aim of this study is to compare the erectile function and penile size of patients undergoing HIFU or TCAP. Methods Patients with a preoperative erectile function domain of the International Index of Erectile Function (IIEF-EF) score ≥26 were prospectively included. All patients were preoperatively evaluated by IIEF-EF and penile color Doppler ultrasound. Penile length and circumference were measured in flaccidity and at maximum erection. At 6, 12, 18, 24, 36 months after surgery, patients were assessed with the same protocol. Main Outcome Measures IIEF-EF score, penile color Doppler ultrasound, penile length, and circumference at different time points. Results There were 55 patients in the HIFU group and 47 in the TCAP group. At each time point, there were significant differences in mean IIEF-EF scores and penile color Doppler results between the two groups. At 36 months, TCAP patients experienced lower erectile function recovery rate compared with HIFU patients (TCAP=46.8%; HIFU=65.5%; P = 0.021). No significant decreases in penile length and circumference were found in the two groups (all P values ≥0.05). Conclusions Our data demonstrate TCAP caused significantly decreased erectile function than HIFU. We found no change in penile size after HIFU or TCAP. The option of HIFU may be more attractive to the patient who wants to avoid ED afterward, to maintain their quality of life.

Calpain-2 may contribute to the promoter methylation of CRMP4 to repress its transcription, leading to the metastasis of PCa via enhancing VEGFC expression.

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