The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma

• Type of Material: Article
• Authors: Sridevi Yadavilli, Children's National Health System; Joseph Scafidi, Children's National Health System; Oren J. Becher, Duke University; Amanda M. Saratsis, Ann & Robert H. Lurie Children's Hospital of Chicago; Rebecca L. Hiner, Memorial Sloan Kettering Cancer Center; Madhuri Kambhampati, Children's National Health System; Santi Mariarita, Childrens Hospital of Philadelphia; Tobey MacDonald, Emory University; Kari-Elise Codispoti, Children's National Health System; Suresh N. Magge, Children's National Health System; Jyoti K. Jaiswal, Children's National Health System; Roger J. Packer, Children's National Health System; Javad Nazarian, Children's National Health System
• Language: English
• Date: 2015-05-20
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Yadavilli et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.3716
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 14
• Start Page: 12141
• End Page: 12155
• Grant/Funding Information: Microscopic analysis was carried out at the CRI Light Microscopy and Image Analysis Core supported by CRI and NIH grant P30HD040677.; Smashing Walnuts Foundation (JN), Piedmont Community Foundation (JN), Childhood Brain Tumor Foundation (JN), Isabella Kerr Molina Foundation (JN), Zickler Family Foundation (JN), Musella Foundation (JN), Brain Tumor Foundation for Children (JN), National Brain Tumor Society (NBTS) (JS), NIH K08NS073793 (JS)
• Keywords: CELL; NG2; glioma; CHONDROITIN SULFATE PROTEOGLYCAN; MELANOMA; DIPG; SUBTYPES; Science & Technology; K27M MUTATION; PDGF; MALIGNANT PROGRESSION; MARKER; Life Sciences & Biomedicine; histone 3; Cell Biology; EXPRESSION; TUMORS; Oncology; BRAIN-STEM GLIOMAS
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro. NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation.