MiR-135a Inhibits Cancer Stem Cell-Driven Medulloblastoma Development by Directly Repressing Arhgef6 Expression

Katayoun Hemmesi, Mario Leonardo Squadrito, Pieter Mestdagh, Valentina Conti, Manuela Cominelli, Ignazio S. Piras, Lucia Sergi Sergi, Sara Piccinin, Roberta Maestro, Pietro L. Poliani, Frank Speleman, Michele De Palma, Rossella Galli

Research output: Contribution to journalArticle

Abstract

microRNAs (miRNAs) are short noncoding RNAs, which regulate gene expression post-transcriptionally and play crucial roles in relevant biological and pathological processes. Here, we investigated the putative role of miRNAs in modulating the tumor-initiating potential of mouse medulloblastoma (MB)-derived cancer stem cells (CSCs). We first subjected bona fide highly tumorigenic (HT) CSCs as well as lowly tumorigenic MB CSCs and normal neural stem cells to miRNA profiling, which identified a HT CSC-specific miRNA signature. Next, by cross-checking CSC mRNA/miRNA profiles, we pinpointed miR-135a as a potential tumor suppressor gene, which was strongly downregulated in HT CSCs as well as in the highly malignant experimental tumors derived from them. Remarkably, enforced expression of miR-135a in HT CSCs strongly inhibited tumorigenesis by repressing the miR-135a direct target gene Arhgef6. Considering the upregulation of Arhgef6 in human MBs and its involvement in mediating experimental medulloblastomagenesis, its efficient suppression by miR-135a might make available an effective therapeutic strategy to selectively impair the tumorigenic potential of MB CSCs. Stem Cells 2015;33:1377-1389

Original languageEnglish
Pages (from-to)1377-1389
Number of pages13
JournalStem Cells
Volume33
Issue number5
DOIs
Publication statusPublished - May 1 2015

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Keywords

  • Arhgef6
  • Cancer stem cell
  • Medulloblastoma
  • miR-135a
  • miRNA signature

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Hemmesi, K., Squadrito, M. L., Mestdagh, P., Conti, V., Cominelli, M., Piras, I. S., Sergi, L. S., Piccinin, S., Maestro, R., Poliani, P. L., Speleman, F., De Palma, M., & Galli, R. (2015). MiR-135a Inhibits Cancer Stem Cell-Driven Medulloblastoma Development by Directly Repressing Arhgef6 Expression. Stem Cells, 33(5), 1377-1389. https://doi.org/10.1002/stem.1958