miRNA-708 control of CD44+ prostate cancer initiating cells
Menée in vitro, à l'aide de xénogreffes et sur des échantillons tumoraux, cette étude met en évidence un mécanisme par lequel le micro-ARN 708, en régulant l'expression de CD44 dans les cellules souches cancéreuses, joue un rôle dans le développement et la progression d'un cancer de la prostate
Tumor recurrence in prostate cancer (PCa) has been attributed to the presence of CD44 expressing tumor-initiating cells (TIC). In this study, we report that miR-708 is a key negative regulator of this CD44+ subpopulation of PCa cells, with important implications for diagnosis and prognosis of this disease. 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 PCa. 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 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 PCa patients. Together, our findings suggest that reduced miR-708 expression leads to PCa 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 PCa.