IDH1R132H decreases the proliferation of U87 glioma cells through upregulation of microRNA-128a

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in >70% of secondary glioblastomas and lower-grade gliomas (grades II-III). Among the numerous phenotypic differences between IDH1 mutant and wild-type glioma patients, the most salient is an improved survival rate for patients with a mutation. MicroRNAs (miRNAs) are a class of small, non-coding, single-stranded RNAs that can negatively regulate gene expression at the post-transcriptional level, predominantly by binding to the 3'-untranslated region of their target mRNAs. The dysregulated expression of several miRNAs has been reported to modulate glioma progression; however, it is unclear whether mutations in IDH1 regulate glioma cell proliferation through miRNA dysregulation. In the present study, stable overexpression of IDH1(WT) or IDH1(R132H) was established in the U87 glioma cell line. It was found that IDH1(R132H) decreased cell proliferation of U87 glioma cells by inducing the expression of the miRNA miR-128a. This process was dependent on the transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha), which binds to a hypoxia response element in the promoter of miR-128a. Furthermore, miR-128a negatively regulated the expression of B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1), which is involved in suppressing cell proliferation. These findings suggest that the IDH1(R132H)-HIF-1 alpha-miR-128a-Bmi-1 pathway is involved in glioma cell proliferation.