MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1

Oncotarget. 2013 May;4(5):665-76. doi: 10.18632/oncotarget.928.

Abstract

Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Differentiation
  • Cell Movement / genetics
  • Cell Proliferation
  • DNA Methylation
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Hedgehog Proteins / biosynthesis
  • Homeodomain Proteins / biosynthesis
  • Humans
  • Membrane Proteins
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nanog Homeobox Protein
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplastic Stem Cells / cytology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / metabolism
  • Octamer Transcription Factor-3 / biosynthesis
  • Promoter Regions, Genetic / genetics
  • Receptors, CXCR4 / biosynthesis*
  • SOXB1 Transcription Factors / biosynthesis
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • CXCR4 protein, human
  • GLIPR1 protein, human
  • Hedgehog Proteins
  • Homeodomain Proteins
  • MIRN137 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Receptors, CXCR4
  • SHH protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors