MicroRNA-21 promotes glioblastoma tumorigenesis by downregulating IGFBP3 [Molecular Bases of Disease]

July 24th, 2014 by Yang, C. H., Yue, J., Pfeffer, S. R., Fan, M., Paulus, E., Hosni-Ahmed, A., Sims, M., Qayyum, S., Davidoff, A. M., Handorf, C. R., Pfeffer, L. M.

Despite advances in surgery, imaging, chemotherapy and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; more than 70% of GBM patients die within 2 years of diagnosis. In many human cancers the microRNA miR-21 is overexpressed and accumulating evidence indicates it functions as an oncogene. Here we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro, and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been previously identified. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro, and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression, and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma, and suggest that the oncogenic miRNA miR-21 downregulates the expression of IGFBP3 which acts as a tumor suppressor in human glioblastoma.