Abstract 2528: miR-452 inhibits migration and invasion of prostate cancer cells by targeting E3 ubiquitin ligase-1 (WWP1)
Authors: Kojima Satoko , Goto Yusuke , Kurozumi Akira , Kato Mayuko , Okato Atsushi , Arai Takayuki , Ichikawa Tomohiko , Naya Yukio , Seki Naohiko 
Published: July 2017

Introduction: Most prostate cancer (PCa) patients initially respond to androgen-deprivation therapy (ADT), but eventually acquire resistance to ADT and progress to castration-resistant prostate cancer (CRPC), resulting in metastasis causing PCa death. We have developed the microRNA (miRNA) expression signature of PCa using clinical specimens and determined the target genes of the tumor suppressive miRNAs, whose expressions are significantly decreased in PCa specimens. Based on the signature, our previous study revealed that miR-224 functions as a tumor suppressor, especially contributes to cancer cell metastasis directly targeting miR-224-TPD52 signaling. In human genome, miR-452 is located nearby tumor-suppressive miR-224, forming clustered miRNAs on chromosome Xq28 region. The aim of the study was to investigate the functional significance of miR-452 and to identify novel miR-452-mediated cancer pathways and responsible genes in PCa cells.

Material and methods: Clinical prostate specimens were obtained from patients admitted to the Teikyo University Chiba Medical Center from 2008 to 2013. Ninety-two patients with elevated PSA levels underwent transrectal prostate needle biopsy, and three patients who died of CRPC underwent autopsies. PCa tissues (n=54), noncancerous prostate tissues (non-PCa, n=36), were used for analysis of expression levels of miRNAs. Functional studies of differentially expressed miRNAs were analyzed using PC3 and DU145 cells. The influence on CRPC-free survival of expression levels of miRNA was estimated using the Kaplan-Meier methods. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miRNAs.

Results: (The miRNA expression signature of PCa specimens showed that the cluster miRNAs miR-224 was significantly downregulated, suggesting that this miRNA may act as tumor suppressor.) Clinical data using advanced PCa showed that low expression of miR-452 predicted a short duration of progression to CRPC. Restoration of miR-452 in PC3 and DU145 cells revealed significant inhibition of cancer cell migration and invasion. WW domain-containing E3 ubiquitin protein ligase-1 (WWP1) was confirmed as a direct target of miR-452 by in vitro transfection of miR-452 and Luciferase assay. Knockdown of the expression of WWP1 using siRNA showed inhibiting cell migration and invasion in PC3 and DU145 cells. Immunohistochemistry showed overexpressed WWP1 in advanced PCa.

Conclusions: Loss of the tumor suppressive miR-452 enhanced migration and invasion in PCa cells. Regulation of the miR-452-WWP1 axis contributed to PCa cell migration and invasion, and elucidation of downstream signaling of this axis will provide new insights into the mechanisms of (progression to CRPC) metastasis of PCa.

Citation Format: Satoko Kojima, Yusuke Goto, Akira Kurozumi, Mayuko Kato, Atsushi Okato, Takayuki Arai, Tomohiko Ichikawa, Yukio Naya, Naohiko Seki. miR-452 inhibits migration and invasion of prostate cancer cells by targeting E3 ubiquitin ligase-1 (WWP1) [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 2528. doi:10.1158/1538-7445.AM2017-2528