MiR-1253 exerts tumor-suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7-H3).
Ranjana K Kanchan, Naveenkumar Perumal, Pranita Atri, Ramakanth Chirravuri Venkata, Ishwor Thapa, David L Klinkebiel, Andrew M Donson, Deborah Perry, Michael Punsoni, Geoffrey A Talmon, Donald W Coulter, Daniel R Boue', Matija Snuderl, Mohd W Nasser, Surinder K Batra, Rajeev Vibhakar, Sidharth Mahapatra
Author Information
Ranjana K Kanchan: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Naveenkumar Perumal: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Pranita Atri: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Ramakanth Chirravuri Venkata: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Ishwor Thapa: School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE.
David L Klinkebiel: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Andrew M Donson: Morgan Adams Pediatric Brain Tumor Research Program, University of Colorado School of Medicine, Denver, CO.
Deborah Perry: Department of Pathology, Children's Hospital and Medical Center, Omaha, NE.
Michael Punsoni: Department of Pathology, University of Nebraska Medical Center, Omaha, NE.
Geoffrey A Talmon: Department of Pathology, University of Nebraska Medical Center, Omaha, NE.
Donald W Coulter: Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE.
Daniel R Boue': Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and the Ohio State University, Columbus, OH.
Matija Snuderl: Department of Pathology, New York University Langone Health, New York, NY.
Mohd W Nasser: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Surinder K Batra: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE.
Rajeev Vibhakar: Morgan Adams Pediatric Brain Tumor Research Program, University of Colorado School of Medicine, Denver, CO.
Sidharth Mahapatra: Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE. ORCID
Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR-1253, a brain-enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR-1253 confers novel tumor-suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR-1253. We then explored the anti-tumorigenic properties of miR-1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high-throughput screening. Deregulation of miR-1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de-methylation of miR-1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR-1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR-1253. These data reveal novel tumor-suppressive properties for miR-1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.
