title: miR-135a Inhibits Cancer Stem Cell-Driven Medulloblastoma Development by Directly Repressing Arhgef6 Expression.
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.
authors: Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
authors: Katayoun
authors: K
authors: Hemmesi
authors: Mario Leonardo
authors: ML
authors: Squadrito
authors: Pieter
authors: P
authors: Mestdagh
authors: Valentina
authors: V
authors: Conti
authors: Manuela
authors: M
authors: Cominelli
authors: Ignazio S
authors: IS
authors: Piras
authors: Lucia Sergi
authors: LS
authors: Sergi
authors: Sara
authors: S
authors: Piccinin
authors: Roberta
authors: R
authors: Maestro
authors: Pietro L
authors: PL
authors: Poliani
authors: Frank
authors: F
authors: Speleman
authors: Michele
authors: M
authors: De Palma
authors: Rossella
authors: R
authors: Galli
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002449:Cell Aggregation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D020869:Gene Expression Profiling; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C576604:Arhgef6 protein, mouse; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D016159:Tumor Suppressor Protein p53
keywords: Arhgef6; Cancer stem cell; Medulloblastoma; miR-135a; miRNA signature