Introduction

Due to its metastatic nature, patients with castration-resistant prostate cancer (CRPC) are difficult to cure and very poor prognosis. To date, there is no effective therapeutic resume for this disease. Therefore, understanding molecular mechanisms of promoting metastasis in CRPC would help to improve therapies for the disease. _x000D_ Currently, numerous studies have indicated that microRNAs (miRNAs) are aberrantly expressed in several cancers, including CRPC. In this study, we constructed a miRNA expression signature to identify miRNA regulated RNA networks in CRPC using autopsy specimens from patients with androgen deprivation therapy (ADT) failure. Based on the signature, dual-strands of pre-miR-145 (miR-145-5p and miR-145-3p) were significantly reduced in CRPC specimens. We focused on the passenger strand miR-145-3p that was significantly reduced in CRPC tissues. The aim of this study was to investigate the functional significance of miR-145-3p and its regulated RNA networks in CRPC._x000D_

Methods

Expression levels of miR-145-3p were evaluated in prostate needle biopsy specimens and autopsy CRPC specimens. Gain-of-function studies were performed by miR-145-3p transfection into PCa cells. Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-145-3p in PCa cells. TCGA database was applied to analyze cohort of CRPC patients.

Results

Downregulation of miR-145-3p was validated in hormone naive PCa and CRPC specimens (P < 0.0001). Patients with lower expression of miR-145-3p tend to have shorter BCR-free interval (P = 0.0739). Restoration of miR-145-3p significantly inhibited cancer cell migration and invasion in PCa cell lines (P < 0.0001). We identified 4 responsible genes (MELK, NCAPG, BUB1 and CDK1) by miR-145-3p regulation. The expressions of MELK, NCAPG, BUB1 and CDK1 were significantly elevated as tumour stage and lymph node stage advanced and all four genes significantly predicted disease-free survival of PCa patients (P < 0.0001, P = 0.0002, P < 0.0001 and P < 0.0001, respectively). Moreover, these four genes were overexpressed in metastatic lesions of CRPC specimens by immunohistochemistry.

Conclusions

Dual-strand of tumor-suppressors, miR-145-5p and miR-145-3p, were identified based on miRNA signature. miR-145-3p regulated RNA networks were deeply involved in CRPC pathogenesis. Small RNA sequencing for lethal CRPC specimens and current in silico approaches provide us with novel therapeutic strategies for CRPC.

Funding

none