Abstract 5322: CD44+ prostate cancer cells are regulated by microRNA-708: A novel role of microRNA with potential prognostic and diagnostic significance in prostate cancer .

Abstract

Abstract A challenging aspect of prostate cancer (PCa) is the high rates of recurrence associated with the disease. About 40% of men with localized prostate cancer suffer from relapse after initial therapy. In these cases, androgen ablation therapy is used to reduce tumor burden/circulating PSA to low or undetectable limits. However, most patients suffer from disease recurrence, as monitored by rising PSA and tumor progression to hormone refractory/castration resistant prostate cancer that is essentially untreatable. Tumor recurrence has been attributed to the existence of tumor-initiating cells (TIC) within the bulk of the tumor; CD44 is an important marker for these cells. In this study, we demonstrate that miR-708 is a key negative regulator of CD44+ subpopulation of PCa cells. miR-708 was underexpressed in CD44+ cells from PCa xenografts. Reconstitution of miR-708 in PCa cell lines or CD44+ PCa cells led to decreased tumorigenicity in vitro. Intratumoral delivery of synthetic miR-708 oligonucleotides triggered regression of established tumors in a murine xenograft model of human prostate cancer. Conversely, miR-708 silencing in a purified CD44- population of PCa cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708. Also, we identified Androgen Receptor (AR) and the serine/threonine kinase AKT2, a member of the PI3K/AKT signaling pathway as functional targets of miR-708. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression and recurrence in prostate cancer patients. In view of these results we propose that reduced miR-708 expression leads to prostate cancer initiation, progression and development by regulating expression of CD44, AR, AKT2, which in turn regulate proliferative, invasive and migratory abilities of prostate cancer cells. Therefore, miR-708 may represent a novel therapeutic target for prostate cancer. Citation Format: Sharanjot Saini, Sumit Arora, Shahana Majid, Varahram Shahryari, Soichiro Yamamura, Inik Chang, Takeshi Chiyomaru, Shinichiro Fukuhara, Guoren Deng, Yuichiro Tanaka, Rajvir Dahiya. CD44+ prostate cancer cells are regulated by microRNA-708: A novel role of microRNA with potential prognostic and diagnostic significance in prostate cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5322. doi:10.1158/1538-7445.AM2013-5322