Abstract 3438: Dual-strands pre-microRNA-150 (miR-150-5p and miR-150-3p) act as tumor suppressor in prostate cancer

Abstract

Abstract Background: Prostate cancer (PCa) is the second most common cause of cancer and the sixth leading cause of cancer death among men in the world. Androgen signaling through the androgen receptor (AR) is an important oncogenic pathway for PCa progression. The initial response rate of PCa to androgen deprivation therapy (ADT) can be up to 80%, but most patients experience disease relapse and progress to castration-resistant prostate cancer (CRPC). Although several clinical trials, such as molecularly-targeted therapies for CRPC have been carried out, these treatments provide limited benefits and, are not curative. Therefore, identification of effective biomarkers for detection of CRPC and understanding the molecular mechanisms of androgen-independent signaling and metastatic signaling pathways underlying PCa using current genomic approaches would help to improve therapies for and prevention of the disease. Currently, numerous studies have indicated that 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 ADT. Based on the signature, dual-strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly reduced in CRPC specimens. The aim of this study was to investigate the functional significance of both strands of miR-150-5p and miR-150-3p and these miRNAs regulated RNA networks in CRPC. Results: Downregulation of miR-150-5p and miR-150-3p were validated in hormone naive PCa and CRPC specimens compared to non-cancerous prostate tissues (p < 0.0001). Restoration of miR-150-5p and miR-150-3p significantly suppressed cancer cell migration and invasion in PCa cell lines (P < 0.0001). Gene expression data and in silico database analysis showed that Sparc/Osteonectin, Cwcv AND Kazal-Like Domains Proteoglycan 1 (SPOCK1) was regulated by both miRNAs. Knockdown of SPOCK1 inhibited cancer cell aggressiveness. Overexpression of SPOCK1 was observed in PCa clinical specimens. Conclusions: In miRNA biogenesis, it is the general consensus that processing of the pre-miRNA through Dicer1 generates a miRNA duplex (a passenger strand and a guide strand), and that the passenger strand has degradation and no regulatory activity and disintegrates in cells. Our present data showed that both strands of pre-miR-150 (miR-150-5p and miR-150-3p) inhibited cancer cell aggressiveness, suggesting these miRNAs as tumor-suppressors. Identification of miRNA-mediated cancer networks may provide novel molecular pathogenesis of the disease. Citation Format: Atsushi Okato, Takayuki Arai, Akira Kurozumi, Mayuko Kato, Yusuke Goto, Keiichi Koshizuka, Satoko Kojima, Tomohiko Ichikawa, Naohiko Seki. Dual-strands pre-microRNA-150 (miR-150-5p and miR-150-3p) act as tumor suppressor in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3438. doi:10.1158/1538-7445.AM2017-3438