Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease

Acta Neuropathologica Communications

D. R. Esfahani¹  P. Ozark²  E. Bartom²  S. An³  J. Qi³  T. Huang³  C. D. James⁴  R. Hashizume⁴  A. M. Saratsis⁵  C. M. Horbinski⁶  E. R. Bonner⁷ 

[1] 0000 0001 2175 0319, grid.185648.6, Department of Neurological Surgery, University of Illinois at Chicago, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0004 0388 2248, grid.413808.6, Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0001 2299 3507, grid.16753.36, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0004 0482 1586, grid.239560.b, Center for Genetic Medicine, Children’s National Health System, 20010, Washington, DC, USA;0000 0004 1936 9510, grid.253615.6, Institute for Biomedical Sciences, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA;

关键词: Tenascin-C;    Diffuse midline glioma;    Diffuse intrinsic pontine glioma (DIPG);    Histone H3 mutation (H3K27 M);   

DOI  :  10.1186/s40478-019-0727-1

来源: publisher

【 摘 要 】

Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increased expression of Tenascin-C (TNC) protein in DIPG cerebrospinal fluid and tumor tissue relative to normal specimens. TNC is an extracellular matrix (ECM) glycoprotein that mediates cell-matrix interactions, guides migrating neurons during normal brain development and is thought to maintain the periventricular stem cell niche in the developing brain. Tumor TNC expression is reported in adult glioma and other cancers. However, the pattern and effects of TNC expression in DIPG has not been previously explored. Here, we characterize TNC expression in patient derived pediatric supratentorial HGG (n = 3) and DIPG (n = 6) cell lines, as well as pediatric glioma tumor (n = 50) and normal brain tissue specimens (n = 3). We found tumor specific TNC gene and protein overexpression that directly correlated with higher tumor grade (WHO III and IV, p = 0.05), H3K27 M mutation (p = 0.012), shorter progression free survival (p = 0.034), and poorer overall survival (0.041) in association with these factors. TNC knockdown via lentiviral shRNA transfection of HGG (n = 1) and DIPG (n = 3) cell lines resulted in decreased cell proliferation, migration, and invasion in vitro (p < 0.01), while TNC cDNA transfection resulted in increased cell migration, invasion and proliferation (p < 0.01) as well as altered cell morphology in H3K27 M mutant DIPG lines. Whole transcriptome sequencing analysis (RNA-Seq) on DIPG (n = 3) and HGG (n = 2) cell lines after TNC cDNA, shRNA, and empty vector control transfection revealed the effects of TNC expression level on global gene expression profiles. Together, our findings reveal TNC expression in DIPG in association with H3K27 M mutation and VEGF signaling, and suggest that TNC may contribute to DIPG tumor phenotype, and serve as a clinically detectable biomarker for DIPG.

【 授权许可】

CC BY