Abstract
To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase- associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor- binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor-binding protein-2 protein (P = .027). Insulin-like growth factor- binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1-mediated migration, but not insulin-like growth factor-2-mediated migration. However, insulin-like growth factor-binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor-binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Astrocytoma / genetics*
-
Astrocytoma / metabolism
-
Astrocytoma / physiopathology
-
Biomarkers, Tumor / genetics
-
Brain Neoplasms / genetics*
-
Brain Neoplasms / metabolism
-
Brain Neoplasms / physiopathology
-
Catalytic Domain / drug effects
-
Catalytic Domain / genetics
-
Cell Line, Tumor
-
Cell Transformation, Neoplastic / genetics
-
Child
-
DNA Repair / drug effects
-
DNA Repair / genetics*
-
DNA-Activated Protein Kinase / chemistry
-
DNA-Activated Protein Kinase / genetics*
-
DNA-Activated Protein Kinase / metabolism
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics
-
Gene Expression Regulation, Neoplastic / genetics*
-
Humans
-
Insulin-Like Growth Factor Binding Protein 2 / genetics*
-
Insulin-Like Growth Factor Binding Protein 2 / metabolism
-
Insulin-Like Growth Factor Binding Protein 2 / pharmacology
-
Neoplasm Invasiveness / genetics
-
Neoplasm Metastasis / genetics
-
Nuclear Proteins / chemistry
-
Nuclear Proteins / genetics*
-
Nuclear Proteins / metabolism
-
Receptor Protein-Tyrosine Kinases / genetics
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
Substances
-
Biomarkers, Tumor
-
Insulin-Like Growth Factor Binding Protein 2
-
Nuclear Proteins
-
Receptor Protein-Tyrosine Kinases
-
DNA-Activated Protein Kinase
-
PRKDC protein, human