miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47.
The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. During this process, the role of microRNAs (miRs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify the miR involved in leptomeningeal dissemination and to elucidate its biological functional mechanisms.



We analyzed the miR expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. Differentially expressed miRs (DEmiRs) were validated in 29 medulloblastoma tissues and three medulloblastoma cell lines. The biological functions of the selected miRs were evaluated using in vitro and in vivo studies.



A total of 12 DEmiRs were identified in medulloblastoma with seeding, including miR-192. The reduced expression of miR-192 was confirmed in the tumor seeding group and in the medulloblastoma cells. Overexpression of miR-192 inhibited cellular proliferation by binding DHFR. miR-192 decreased cellular anchoring via the repression of ITGAV, ITGB1, ITGB3, and CD47. Animals in the miR-192-treated group demonstrated a reduction of spinal seeding (P < 0.05) and a significant survival benefit (P < 0.05).



Medulloblastoma with seeding showed specific DEmiRs compared with those without. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring ability.
Department of Neurosurgery, Dongguk University Ilsan Hospital, Dongguk University, Seoul, Korea.
Seung Yeob
SY
Yang
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.|Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Seung Ah
SA
Choi
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.|Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.|Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea.
Ji Yeoun
JY
Lee
College of Pharmacy, Sunchon National University, Jeonnam, Korea.
Ae-Kyung
AK
Park
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.|Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Kyu-Chang
KC
Wang
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.|Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Ji Hoon
JH
Phi
Department of Neurosurgery, Dongguk University Ilsan Hospital, Dongguk University, Seoul, Korea.
Eun Jung
EJ
Koh
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.|Translational Genomics Laboratory, Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
Woong-Yang
WY
Park
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Sung-Hye
SH
Park
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
Do Won
DW
Hwang
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Hee Won
HW
Jung
Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.|Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Seung-Ki
SK
Kim
D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D016023:Integrins / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055756:Meningeal Carcinomatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014162:Transfection
D051928:CD47 Antigen; C497894:CD47 protein, human; D016023:Integrins; C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D013762:Tetrahydrofolate Dehydrogenase
CD47; dihydrofolate reductase; integrins; medulloblastoma; microRNA-192