title: miR128-1 inhibits the growth of glioblastoma multiforme and glioma stem-like cells via targeting BMI1 and E2F3.
abstract: MicroRNA128-1 (miR128-1), as a brain-specific miRNA, is downregulated in glioblastoma multiforme (GBM) and closely associated with the progression of GBM. However, the underlying molecular mechanism of the downregulation and its role in the regulation of tumorigenesis and anticancer drug resistance in GBM remains largely unknown. In the current study,we found that miR128-1 was downregulated in GBM and glioma stem-like cells (GSCs). Intriguingly, treatment with the DNA methylation inhibitors 5-Aza-CdR (Aza) and 4-phenylbutyric acid (PBA) resulted in miR128-1 upregulation in both GBM cells and GSCs. Either forced expression of miR128-1 or Aza/PBA treatment inhibited tumor cell proliferation, migration and invasion in vitro. Moreover, overexpression of miR128-1 inhibited the growth of transplant tumor in vivo. BMI1 and E2F3 were found to be direct targets of miR128-1 and downregulated by miR128-1 in vitro and in vivo. Our results revealed a mechanism of methylation that controls miR128-1 expression in GBM cells and GSCs and indicate miR128-1 could function as a tumor suppressor in GBM by negatively regulating tumor cell proliferation, invasion and self-renewal through direct targeting BMI1 and E2F3. Our findings suggest that DNA methylation inhibitors are potential agents for GBM treatment by upregulating miR-128-1.
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.|School of Pharmacy and Medical Sciences, Faculty of Health Sciences, University of South Australia, Adelaide SA 5000, Australia.
authors.forename: Zheng-Nan
authors.initials: ZN
authors.lastname: Shan
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Zhao-Hua
authors.initials: ZH
authors.lastname: Gui
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: School of Pharmacy and Medical Sciences, Faculty of Health Sciences, University of South Australia, Adelaide SA 5000, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Anhui Provincial Hospital affiliated to Anhui Medical University and Anhui Provincial Cancer Hospital, Hefei 230031, China.
authors.forename: Jie
authors.initials: J
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D004791:Enzyme Inhibitors; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D015254:DNA Modification Methylases; D063150:Polycomb Repressive Complex 1
keywords: BMI1; DNA methylation; E2F3; glioblastoma multiforme; miR128-1