Abstract 145: MicroRNA-23b Expression is Regulated by VHL and effects on Glioma Cell survival and invasion

Abstract

Abstract Background Glioblastoma is the most common malignant primary brain tumor in adults. While increasing evidence indicates that the deregulation of miRNAs is involved in a wide range of human cancers, the roles and potential mechanisms of miRNA in glioma development and progression are still largely unknown. Methods The expression of miR-23b in 48 clinical samples and five glioma cell lines with different grades was examined by FISH and qRT-PCR. Flow cytometry, Annexin V method, Colony formation assay, and Transwell cell invasion test were used to detect the proliferation and invasive activity of the tumor cells before and after transfection with AS-miR-23b of glioma cells. Luciferase assay and western blot analysis were used to examine that VHL is a direct target of miR-23b. In vivo anti-glioma effect of AS-miR-23b was investigated using subcutaneous xenograft models. Results We identified that expression of miR-23b is elevated in both glioma tissue samples and glioma cells by real-time PCR and FISH analyses. Knock-down of miR-23b expression triggered growth inhibition, induced apoptosis and suppressed invasion of glioma cells in vitro. Luciferase assay and western blot analysis revealed that VHL is a direct target of miR-23b. As such, restored expression of VHL inhibited glioma cell survival and induced apoptosis. Mechanistic investigation revealed that miR-23b deletion decreased HIF-1α/VEGF expression and suppressed β-catenin/Tcf-4 transcription activity in a VHL-dependent manner. Furthermore, expression of VHL was inversely correlated with miR-23b in glioblastoma samples and was predictive of patient survival in a retrospective analysis. Conclusion In summary, we demonstrate that down-regulation of miR-23b inhibits survival and invasion of glioma by repressing expression of VHL. Genetic restoration of VHL bypassed the effects of miR-23b overexpression, suppressing the ranscriptional activities of both the HIF/VEGF and β-catenin/Tcf-4 pathways. Based upon these observations, we propose that anti-angiogenic therapy for glioma could benefit from adjuvent miRNA therapy targeting the HIF1α and β-catenin/Tcf-4 pathways. 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 145. doi:1538-7445.AM2012-145