title: Suppression of tumorigenicity by microRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme.
abstract: Deregulation of microRNAs (miRNAs) is implicated in tumor progression. We attempt to identify the tumor suppressive miRNA not only down-regulated in glioblastoma multiforme (GBM) but also potent to inhibit the oncogene EZH2, and then investigate the biological function and pathophysiologic role of the candidate miRNA in GBM. In this study, we show that miRNA-138 is reduced in both GBM clinical specimens and cell lines, and is effective to inhibit EZH2 expression. Moreover, high levels of miR-138 are associated with long overall and progression-free survival of GBM patients from The Cancer Genome Atlas dataset (TCGA) data portal. Ectopic expression of miRNA-138 effectively inhibits GBM cell proliferation in vitro and tumorigenicity in vivo through inducing cell cycles G1/S arrest. Mechanism investigation reveals that miRNA-138 acquires tumor inhibition through directly targeting EZH2, CDK6, E2F2 and E2F3. Moreover, an EZH2-mediated signal loop, EZH2-CDK4/6-pRb-E2F1, is probably involved in GBM tumorigenicity, and this loop can be blocked by miRNA-138. Additionally, miRNA-138 negatively correlates to mRNA levels of EZH2 and CDK6 among GBM clinical samples from both TCGA and our small amount datasets. In conclusion, our data demonstrate a tumor suppressive role of miRNA-138 in GBM tumorigenicity, suggesting a potential application in GBM therapy.
authors.affiliation: Department of Neurology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Qiu
authors.forename: Daquan
authors.initials: D
authors.lastname: Huang
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
authors.forename: Fangcheng
authors.initials: F
authors.lastname: Li
authors.forename: Xiangping
authors.initials: X
authors.lastname: Li
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: Glioblastoma multiforme/microRNA-138/EZH2/CDK6/tumorigenicity/TCGA