Pirin: a potential novel therapeutic target for castration‐resistant prostate cancer regulated by miR‐455‐5p

• Published in: Molecular oncology 2019-02, Vol.13 (2), p.322-337
• Main Authors: Arai, Takayuki, Kojima, Satoko, Yamada, Yasutaka, Sugawara, Sho, Kato, Mayuko, Yamazaki, Kazuto, Naya, Yukio, Ichikawa, Tomohiko, Seki, Naohiko
• Format: Article
• Language: English
• Subjects: Androgens; Antineoplastic Agents - pharmacology; Argonaute Proteins - metabolism; Autopsy; bisamide; Cancer therapies; Carrier Proteins - metabolism; Castration; castration‐resistant prostate cancer; Cell growth; Cell Line, Tumor; Cell migration; Chromosome 3; Chromosome 5; Disease-Free Survival; Experiments; Gene Expression Regulation, Neoplastic; Genomes; Humans; Insulin-like growth factor-binding protein 3; Male; Menopause; Metastasis; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; miR‐455‐5p; Molecular Targeted Therapy; Nuclear Proteins - metabolism; Oncogenes; Pathogenesis; Physiology; pirin; Polymerase chain reaction; Prognosis; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; siRNA; Studies; Therapeutic applications; Vectors (Biology)
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12405

Androgen deprivation therapy is frequently used to treat prostate cancer (PCa), but resistance can occur, a condition known as castration‐resistant prostate cancer (CRPC). Thus, novel approaches for identification of CRPC are important for designing effective PCa treatments. Analysis of microRNA (miRNA) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR‐455‐duplex (miR‐455‐5p and miR‐455‐3p, respectively) acted as antitumor miRNAs in PCa cells. The involvement of miRNA passenger strands in cancer pathogenesis is a novel concept for miRNA functionality. Based on a large patient cohort in The Cancer Genome Atlas, expression of eight miR‐455‐5p/‐3p target genes (PIR: P = 0.0137, LRP8: P = 0.0495, IGFBP3: P = 0.0172, DMBX1: P = 0.0175, CCDC64: P = 0.0446, TUBB1: P = 0.0149, KIF21B: P = 0.0336, and NFAM1: P = 0.0013) was significantly associated with poor prognosis of PCa patients. Here, we focused on PIR (pirin), a highly conserved member of the cupin superfamily. PIR expression was directly regulated by miR‐455‐5p, and PIR overexpression was detected in hormone‐sensitive prostate cancer (HSPC) surgical specimens and CRPC autopsy specimens. Loss‐of‐function assays using siRNA or an inhibitor (bisamide) showed that downregulation of PIR expression blocked cancer cell migration and invasion. Moreover, the miR‐455‐5p/PIR axis contributed to cancer cell aggressiveness. These results suggest that PIR might be a promising diagnostic marker for HSPC and CRPC. Furthermore, CRPC treatment strategies targeting PIR may be possible in the future. Identification of antitumor miRNAs, including miRNA passenger strands, may contribute to the development of new diagnostic markers and therapeutic strategies for CRPC. Downregulation of miR‐455‐5p and upregulation of PIR were significantly associated with poor prognosis of patients with prostate cancer (PCa). Aberrant expression of PIR was observed in PCa clinical specimens including castration‐resistant prostate cancer. PIR might be a promising diagnostic marker and a novel therapeutic target for PCa.