Liu Q.,Central South University |
Liu Q.,Institute of Skull Base Surgery and Neurooncology |
Zhang C.,Central South University |
Yuan J.,Central South University |
And 10 more authors.
Neuro-Oncology | Year: 2015
Background: CD44 is a molecular marker associated with molecular subtype and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting the CD44-high gliomas. Methods: Protein tyrosine kinase 7 (PTK7) mRNA expression was analyzed based on The Cancer Genome Atlas glioblastoma dataset. PTK7 expression was depleted through lentivirus-mediated short hairpin RNA knockdown. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was used to evaluate cell apoptosis following PTK7 knockdown. Gene expression analysis was performed on Affymetrix microarray. A nude mice orthotopic tumor model was used to evaluate the in vivo effect of PTK7 depletion. Results: PTK7 is highly expressed in CD44-high glioblastoma and predicts unfavorable prognosis. PTK7 knockdown attenuated cell proliferation, impaired tumorigenic potential, and induced apoptosis in CD44-high glioma cell lines. Gene expression analysis identified inhibitor of DNA Binding 1 (Id1) gene as a potential downstream effector for PTK7. Overexpression of Id1 mostly restored the cell proliferation and colony formation attenuated by PTK7 depletion. PTK7 enhanced anchorage-independent growth in normal human astrocytes, which was attenuated by Id1 knockdown. Furthermore, PTK7 regulated Id1 expression through modulating TGF-β/Smad signaling, while pharmacological inhibition on TGF-β/Smad signaling or PTK7/Id1 depletion attenuated TGF-β-stimulated cell proliferation. PTK7 depletion consistently reduced Id1 expression, suppressed tumor growth, and induced apoptosis in a murine orthotopic tumor model, which could be translated into prolonged survival in tumor-bearing mice. Conclusions: PTK7 regulates Id1 expression in CD44-high glioma cell lines. Targeting PTK7 could be an effective strategy for treating glioma with high CD44 expression. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.