title: MicroRNA142-3p promotes tumor-initiating and radioresistant properties in malignant pediatric brain tumors.
abstract: Primary central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT) is an extremely malignant pediatric brain tumor observed in infancy and childhood. It has been reported that a subpopulation of CD133(+) cells isolated from ATRT tumors present with cancer stem-like and radioresistant properties. However, the exact biomolecular mechanisms of ATRT or CD133-positive ATRT (ATRT-CD133(+)) cells are still unclear. We have previously shown that ATRT-CD133(+) cells have pluripotent differentiation ability and the capability of malignant cells to be highly resistant to ionizing radiation (IR). By using microRNA array and quantitative RT-PCR in this study, we showed that expression of miR142-3p was lower in ATRT-CD133(+) cells than in ATRT-CD133(-) cells. miR142-3p overexpression significantly inhibited the self-renewal and tumorigenicity of ATRT-CD133(+) cells. On the contrary, silencing of endogenous miR142-3p dramatically increased the tumor-initiating and stem-like cell capacities in ATRT cells or ATRT-CD133(-) cells and further promoted the mesenchymal transitional and radioresistant properties of ATRT cells. Most importantly, therapeutic delivery of miR142-3p in ATRT cells effectively reduced its lethality by blocking tumor growth, repressing invasiveness, increasing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice. These results demonstrate the prospect of developing novel miRNA-based strategies to block the stem-like and radioresistant properties of malignant pediatric brain cancer stem cells.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Yen
authors.initials: YY
authors.lastname: Lee
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Huang
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Sang-Hue
authors.initials: SH
authors.lastname: Yen
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Yuan-Tzu
authors.initials: YT
authors.lastname: Lan
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Ma
authors.forename: Yang-Hsin
authors.initials: YH
authors.lastname: Shih
authors.forename: Ming-Teh
authors.initials: MT
authors.lastname: Chen
mesh_terms: D000071916:AC133 Antigen; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D002465:Cell Movement; D002470:Cell Survival / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D000067956:Adenylyl Cyclase Inhibitors; D015703:Antigens, CD; D006023:Glycoproteins; C555159:MIRN142 microRNA, human; D035683:MicroRNAs; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9