miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47
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Seung Yeob Yang1,*, Seung Ah Choi2,3,*, Ji Yeoun Lee2,3,4, Ae-Kyung Park5, Kyu-Chang Wang2,3, Ji Hoon Phi2,3, Eun Jung Koh1, Woong-Yang Park6,7, Sung-Hye Park8, Do Won Hwang9, Hee Won Jung3 and Seung-Ki Kim2,3
1 Department of Neurosurgery, Dongguk University Ilsan Hospital, Dongguk University, Seoul, Korea
2 Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, Korea
3 Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
4 Department of Anatomy, Seoul National University College of Medicine, Seoul, Korea
5 College of Pharmacy, Sunchon National University, Jeonnam, Korea
6 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
7 Translational Genomics Laboratory, Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
8 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
9 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
* These authors have contributed equally to this study
Seung-Ki Kim, email:
Keywords: medulloblastoma, microRNA-192, integrins, CD47, dihydrofolate reductase
Received: March 31, 2015 Accepted: October 14, 2015 Published: October 25, 2015
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.
Materials and methods
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.
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