Abstract 3985: MicroRNA-21 regulates Sox2 expression and tumor self-renewal in PDGF-driven glioma

Abstract

Abstract The Platelet-Derived Growth Factor (PDGF) has a known role in the progression of malignant primary brain tumors, glioma, but the mechanisms behind PDGF-driven brain tumor development are still not clarified. MicroRNAs regulate many genes in our genome at a post-transcriptional level. We recently identified microRNA-21 (miR-21) as a target in a retroviral screen for candidate brain tumor initiating genes in mice. To explore a role for miR-21 in brain tumors we used Northern blot and in situ hybridization to show that the expression levels of miR-21 in PDGF-induced mouse brain tumors and primary mouse glioma cell lines were strongly increased as compared to normal mouse brain. In normal fibroblasts, the expression of miR-21 was induced by a number of growth factors, including PDGF-B, suggesting miR-21 is downstream of PDGF signaling. By inhibiting PDGF-B with siRNA in Sox2-expressing mouse glioma initiating cells, we showed that miR-21 expression could be suppressed, followed by a decrease in tumor cell self-renewal. To understand the mechanisms of miR-21 in normal development, we identified miR-21 to be highly expressed during embryonic development and in newborn brain with its expression turned off before postnatal day 7 (P7) in the mouse brain. The expression of miR-21 overlapped with Sox2 expression in embryonic and newborn normal mouse brain, whose expression levels similarly decreased at P7. In situ hybridization of miR-21 and IHC staining of Sox2 showed consistent co-expression in mouse brain tumor specimens. Irreversible depletion of miR-21 by using an LNA-modified siRNA was shown to repress Sox2 in primary mouse brain tumor cells but also in human glioma cell lines. Our data suggest that miR-21 regulates Sox2, maintains the tumor initiating cell population and the progression of PDGF-driven brain tumors which insinuates miR-21 as a promising target for future treatment of glioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2011-3985