Oncotarget

Research Papers:

The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma

Sridevi Yadavilli, Joseph Scafidi, Oren J. Becher, Amanda M. Saratsis, Rebecca L. Hiner, Madhuri Kambhampati, Santi Mariarita, Tobey J. MacDonald, Kari-Elise Codispoti, Suresh N. Magge, Jyoti K. Jaiswal, Roger J. Packer, Javad Nazarian _

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Oncotarget. 2015; 6:12141-12155. https://doi.org/10.18632/oncotarget.3716

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Abstract

Sridevi Yadavilli1, Joseph Scafidi2, Oren J. Becher3, Amanda M. Saratsis4, Rebecca L. Hiner5, Madhuri Kambhampati1, Santi Mariarita6, Tobey J. MacDonald7, Kari-Elise Codispoti8, Suresh N. Magge9, Jyoti K. Jaiswal1,10, Roger J. Packer11 and Javad Nazarian1,10

1 Research Center for Genetic Medicine, Children’s National Health System, Washington, DC, USA

2 Department of Neurology and Center for Neuroscience Research, Children’s National Health System, Washington, DC, USA

3 Department of Pediatrics and Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

4 Division of Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

5 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, NY, USA

6 Department of Pathology and Lab Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

7 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

8 Department of Pathology, Children’s National Health System, Washington, DC, USA

9 Division of Neurosurgery, Children’s National Health System, Washington, DC, USA

10 Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

11 Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DC, USA

Correspondence to:

Javad Nazarian, email:

Keywords: DIPG, NG2, PDGF, histone 3, glioma

Received: March 04, 2015 Accepted: March 11, 2015 Published: March 30, 2015

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.

Author Information

Sridevi Yadavilli

Joseph Scafidi

Oren J. Becher

Amanda M. Saratsis

Rebecca L. Hiner

Madhuri Kambhampati

Santi Mariarita

Tobey J. MacDonald

Kari-Elise Codispoti

Suresh N. Magge

Jyoti K. Jaiswal

Roger J. Packer

Javad Nazarian
Primary Contact  _


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