title: miR-29b attenuates tumorigenicity and stemness maintenance in human glioblastoma multiforme by directly targeting BCL2L2.
abstract: Glioblastoma multiforme (GBM) is the most common malignant brain tumor and exhibits aggressive and invasive behavior. We previously identified four miRNAs-miR-29b, 494, 193a-3p, and 30e-with enhanced expression in GBM following treatment of ionizing radiation by miRNA microarray analysis. In this study, we found that only miR-29b inhibited tumor cell migration and invasion by reducing MMP-2 activity via phospho-AKT/β-catenin signaling, and stimulated a more epithelial-like morphology. Moreover, miR-29b inhibits angiogenesis by attenuating tube formation and the expression of VEGF and Ang-2, and stemness maintenance in GBM cells, as demonstrated by decreasing neurosphere formation and cancer stem cell marker protein expression. These findings support the anti-tumor properties of miR-29b in human GBM cells. Furthermore, miR-29b expression was inversely proportional to that of BCL2L2 mRNA or protein in various cancer cell types. Interestingly, BCL2L2 mRNA is highly expressed in the mesenchymal type of GBM. To further elucidate the relationship between miR-29b and BCL2L2 in GBM, we performed co-transfection reporter assays and determined that miR-29b downregulates BCL2L2 expression by directly binding its 3'UTR. Finally, we confirmed that BCL2L2 repression is of central importance to miR-29b anti-tumor activity using functional assays to examine cell migration, invasion, angiogenesis, and stemness. From these data, we propose that miR-29b may be a useful therapeutic agent in GBM.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.|Research Center for Radio-Senescence, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.|Research Center for Radio-Senescence, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Han
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.|Research Center for Radio-Senescence, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.|Research Center for Radio-Senescence, Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Bae
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2
keywords: BCL2L2; GBM; miR-29b; stemness; tumorigenicity