MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB)

Acta Neuropathologica Communications

Surinder K. Batra¹  Ranjana K. Kanchan¹  Raghupathy Vengoji¹  Naveenkumar Perumal¹  Pranita Atri¹  Mohd W. Nasser¹  Shailendra K. Maurya¹  Ramakanth Chirravuri-Venkata¹  David Klinkebiel¹  Sidharth Mahapatra²  David Doss³  Noah Bastola⁴  Geoffrey A. Talmon⁵  Ishwor Thapa⁶ 

[1] Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA;Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA;Department of Pediatrics, University of Nebraska Medical Center, 68198, Omaha, NE, USA;Department of Biomedical Sciences, Creighton University School of Medicine, 68124, Omaha, NE, USA;Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 63110, St. Louis, MO, USA;Department of Pathology and Microbiology, University of Nebraska Medical Center, 68198, Omaha, NE, USA;School of Interdisciplinary Informatics, University of Nebraska at Omaha, 68182, Omaha, NE, USA;

关键词: 17p13.3;    c-Myc;    Group 3 medulloblastoma;    miR-212-3p;    Nuclear factor I/B;   

DOI  :  10.1186/s40478-021-01299-z

来源: Springer

【 摘 要 】

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.

【 授权许可】

CC BY