Abstract 1459: Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) are involved in castration-resistant prostate cancer pathogenesis
Authors: Kato Mayuko , Kurozumi Akira , Goto Yusuke , Nohata Nijiro , Arai Takayuki , Okato Atsushi , Koshizuka Keiichi , Kojima Satoko , Ichikawa Tomohiko , Seki Naohiko 
Published: July 2017

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer-related death among men in developed countries. Androgen signaling through the androgen receptor (AR) is an important oncogenic pathway for PCa progression. Most patients initially respond to androgen-deprivation therapy (ADT), but eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). Although several clinical trials for CRPC have been carried out, resulting in the availability of novel chemotherapeutic agents, these treatments provide limited benefits and are not considered 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. The discovery of microRNAs (miRNAs) has resulted in major advancements in cancer research. miRNAs are small noncoding RNAs that function to fine tune the expression of protein coding/noncoding RNAs by repressing translation or cleaving RNA transcripts in a sequence-depending manner. The unique characteristic function of miRNAs is to regulate RNA transcripts in human cells. Therefore, dysregulated expression of miRNAs can disrupt tightly regulated RNA networks in cancer cells. miRNAs play critical roles in various biological processes, and their dysregulation is shown in several human cancers. In this study, we constructed the miRNA expression signature of CRPC using clinical specimens because the development of therapeutic strategies is a central theme in the advancement of PCa treatments. Using CRPC expression signature data, we investigated the specific roles of miRNAs in PCa and CRPC oncogenesis by examining differentially expressed miRNAs. Based on the CRPC signature, we focused on the dual strand of pre-miR-145, miR-145-5p and miR-145-3p because these miRNAs were significantly reduced in cancer tissues, suggesting these miRNAs act as antitumor miRNAs in this disease. 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 miRNAs, miR-145-5p and miR-145-3p significantly suppressed cancer cell migration and invasion. Moreover, Kaplan-Meier survival curves showed that low expression of miR-145-3p predicted a short duration of progression to CRPC. Dual strand of pre-miR-145 functioned as tumor suppressors based on the miRNA expression signature of CRPC. Identification of miRNA-mediated cancer networks may provide novel molecular pathogenesis of the disease.

Citation Format: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Nijiro Nohata, Takayuki Arai, Atsushi Okato, Keiichi Koshizuka, Satoko Kojima, Tomohiko Ichikawa, Naohiko Seki. Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) are involved in castration-resistant prostate cancer pathogenesis [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 1459. doi:10.1158/1538-7445.AM2017-1459