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: 9.33). 05/2012; 72(14):3618-30. DOI: 10.1158/0008-5472.CAN-12-0540
Source: PubMed


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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    • "HNRNPK and VEGF-A are direct targets of miR-205 and miR-29b, respectively [95]. Similarly, CD44 and v-akt murine thymoma viral oncogene homolog 2 (AKT2) are direct targets of miR-708 [96]. "
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    Full-text · Article · Apr 2014 · Cancer Cell International
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    • "Through global gene expression profiling, members of the Wnt/catenin signaling pathway and CSC markers were confirmed to be targets of miR-320.19 Similarly, miR-708 was identified to be downregulated in a CD44+ subgroup of PCa cells and was proposed to be a tumor suppressor miR, regulating PCa initiation and progression by targeting CD44 and the serine/threonine kinase AKT2.20 Downregulation of miR-708 was also demonstrated in the lymph nodes and distal metastases in breast cancer, suggesting a metastasis-suppressive role for breast cancer by targeting the endoplasmic reticulum protein neuronatin.21 "
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    • "Altered miRNA expression levels have been reported in most human cancers. In fact, miRNAs can function as oncogenes or as tumor suppressor genes by targeting different steps of the tumorigenesis process, such as initiation, progression, and metastasis [9,10]. Recently, miRNA profiling studies have led to the identification of miRNAs that are aberrantly expressed in breast cancer [11]. "
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