Downregulation of SUN2, a novel tumor suppressor, mediates miR-221/222-induced malignancy in central nervous system embryonal tumors.
Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan, ttwomg99@gmail.com.
Tsung-Han
TH
Hsieh
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan, ttwomg99@gmail.com.
Chen-Li
CL
Chien
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
Yu-Hsiu
YH
Lee
Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Chen-I
CI
Lin
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
Jui-Yu
JY
Hsieh
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Meng-En
ME
Chao
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Da-Jung
DJ
Liu
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Shing-Shiung
SS
Chu
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Wan
W
Chen
Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Shih-Chieh
SC
Lin
Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
Donald Ming-Tak
DM
Ho
School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, National PET/Cyclotron Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan, Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei 112, Taiwan.
Ren-Shyan
RS
Liu
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan, Institute of Biophotonics, National Yang-Ming University, Taipei 112, Taiwan.
Chi-Hung
CH
Lin
Division of Neurosurgery, Department of Surgery, Cheng Hsin General Hospital, Taipei 112, Taiwan, Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan, Cancer Research Center & Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan, hwwang@ym.edu.tw.
Tai-Tong
TT
Wong
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan, Cancer Research Center & Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan, Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan and Department of Education and Research, Taipei City Hospital, Taipei 112, Taiwan hwwang@ym.edu.tw.
Hsei-Wei
HW
Wang
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000401:mortality; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000401:mortality; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics / Q000401:mortality; D018335:Rhabdoid Tumor / Q000235:genetics / Q000401:mortality; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; C525709:MIR221, human; C525710:MIR222, human; C413025:SUN2 protein, human