Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Abstract

MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. Aberrant expression of miRNAs has been shown to be involved in tumorigenesis. We showed that miR-21 was one of the most frequently overexpressed miRNA in human glioblastoma (GBM) cell lines. To explore whether miR-21 can serve as a therapeutic target for glioblastoma, we downregulated miR-21 with a specific antisense oligonucleotide and found that apoptosis was induced and cell-cycle progression was inhibited in vitro in U251 (PTEN mutant) and LN229 (PTEN wild-type) GBM cells; xenograft tumors from antisense-treated U251 cells were suppressed in vivo. Antisense-miR-21-treated cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-21 is known to regulate PTEN and downregulation of miR-21 led to increased PTEN expression both endogenously and in a reporter gene assay, the GBM suppressor effect of antisense-miR-21 is most likely independent of PTEN regulation because U251 has mutant PTEN. Microarray analysis showed that the knockdown of miR-21 significantly altered expression of 169 genes involved in nine cell-cycle and signaling pathways. Taken together, our studies provide evidence that miR-21 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status.