Abstract 181: MIR-18b decreases self-renewal of glioblastoma cancer stem-like cells through targeting NOTCH2, NEDD9, and MEKK1

Abstract

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in human with extremely poor prognosis and new treatment for this deadly disease is desperately needed. Cancer Stem-like cells (CSCs) have been prospectively isolated from GBM and shown required for tumor propagation. We and others have demonstrated recently that differentiation of GBM neurospheres decreases GBM cell propagation both in vitro and in vivo (Zhu et al, Cancer Research, 71:6061-72, 2011). In the current study, we found that miR-18b was up-regulated upon differentiation of GBM neurosphere. When we introduced miR-18b into GBM neurospheres by lentivirus, we found that miR-18b decreases clonogenesis and growth of three different GBM neurosphere lines, indicating that GBM CSC population was reduced by miR-18b. Mechanistically, we found that miR-18b down-regulates luciferase activity of 3′-UTR reporters of NOTCH2, NEDD9, and MEKK1. Furthermore, protein expression of NOTCH2, NEDD9, and MEKK1 are also decreased by miR-18b, suggesting that NOTCH2, NEDD9 and MEKK1 are the direct targets of miR-18b in GBM CSCs. In addition, we have demonstrated previously that NOTCH regulates GBM CSC propagation through pAKT (Fan et al, Stem Cells, 28:5-16, 2010). Here, we found that pAKT and pERK1/2 were also down-regulated in miR-10b infected GBM neurosphere lines, indicating that miR-18b reduces GBM CSC propagation through NOTCH2/pAKT pathways. Taken together, we have demonstrated that miR-18b functions as a tumor suppressor and decreases GBM CSC propagation through targeting NOTCH2, NEDD9, and MEKK1, indicating that miR-18b can be a potential therapeutic molecule to target GBM CSCs and improve GBM treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 181. doi:1538-7445.AM2012-181