title: MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1.
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.
authors.affiliation: Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Bier
authors.forename: Nis
authors.initials: N
authors.lastname: Giladi
authors.forename: Noan
authors.initials: N
authors.lastname: Kronfeld
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Lee
authors.forename: Simona
authors.initials: S
authors.lastname: Cazacu
authors.forename: Susan
authors.initials: S
authors.lastname: Finniss
authors.forename: Cunli
authors.initials: C
authors.lastname: Xiang
authors.forename: Laila
authors.initials: L
authors.lastname: Poisson
authors.forename: Ana C
authors.initials: AC
authors.lastname: deCarvalho
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Elad
authors.initials: E
authors.lastname: Jacoby
authors.forename: Michal
authors.initials: M
authors.lastname: Yalon
authors.forename: Amos
authors.initials: A
authors.lastname: Toren
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Chaya
authors.initials: C
authors.lastname: Brodie
mesh_terms: D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000096:biosynthesis; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008565:Membrane Proteins; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C527276:CXCR4 protein, human; C094538:GLIPR1 protein, human; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C545567:MIRN137 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D019718:Receptors, CXCR4; C509239:SHH protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors