miRNA-708 Control of CD44(+) Prostate Cancer-Initiating Cells

Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, California 94121, USA.
Cancer Research (Impact Factor: 9.28). 05/2012; 72(14):3618-30. DOI: 10.1158/0008-5472.CAN-12-0540
Source: PubMed

ABSTRACT Tumor recurrence in prostate cancer has been attributed to the presence of CD44-expressing tumor-initiating cells. In this study, we report that miR-708 is a key negative regulator of this CD44(+) subpopulation of prostate cancer cells, with important implications for diagnosis and prognosis of this disease. miR-708 was underexpressed in CD44(+) cells from prostate cancer xenografts. Reconstitution of miR-708 in prostate cancer cell lines or CD44(+) prostate cancer 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 prostate cancer cells promoted tumor growth. Functional studies validated CD44 to be a direct target of miR-708 and also identified the serine/threonine kinase AKT2 as an additional target. Clinically, low miR-708 expression was associated significantly with poor survival outcome, tumor progression, and recurrence in patients with prostate cancer. Together, our findings suggest that reduced miR-708 expression leads to prostate cancer initiation, progression, and development by regulating the expression of CD44 as well as AKT2. miR-708 therefore may represent a novel therapeutic target or diagnostic and prognostic biomarker in prostate cancer.

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    • "However, at the protein level, of the genes tested, expression of neuronatin protein was significantly decreased by miR-708 (Figure 3C), consistent with RT-PCR analysis (Figure S3C). We also evaluated AKT2, which was recently reported to be a target of miR-708 in primary prostate cancer (Saini et al., 2012), but did not find it to be suppressed by miR-708 in breast cancer (data not shown). Consistent with the constitutive expression system, doxycycline-mediated acute and conditional expression of miR- 708 also suppressed neuronatin levels (Figure S3D). "
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