Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors: the protein uPAR is a cytoplasmic sequestration factor for Hand-1. Mol Cancer Ther 2014 May;13(5):1309-22
Date
03/14/2014Pubmed ID
24623737DOI
10.1158/1535-7163.MCT-13-0892Scopus ID
2-s2.0-84899886134 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in the tumor-stromal invasive microenvironment in many human cancers, including medulloblastoma. The role of uPAR in tumor progression and angiogenesis has been well characterized. Previously, in medulloblastoma cells, we showed that ionizing radiation (IR)-induced uPAR is a potent activator of cancer stem cell (CSC)-like properties and is associated with various transcription factors that are involved during embryonic development and cancer. In the present study, we show that uPAR protein acts as a cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand-1. The Hand-1 protein plays an essential role in the differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contribution to cancer remain mostly unknown. We also observed that the Hand-1 protein is upregulated in uPAR short hairpin RNA-treated medulloblastoma cells and accompanies sustained cell growth and angiogenesis. Furthermore, IR-induced uPAR overexpression negatively regulates Hand-1 activity and results in the stabilization of angiogenesis-promoting molecules, including hypoxia-inducible factor-1α. Finally, uPAR overexpression and its association with Hand-1 after IR treatment indicate that uPAR is capable of regulating Hand-1 and that uPAR has a role in the process of IR-induced tumor angiogenesis.
Author List
Asuthkar S, Gogineni VR, Rao JS, Velpula KKMESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusAnimals
Basic Helix-Loop-Helix Transcription Factors
Cell Line, Tumor
Cytoplasm
Disease Models, Animal
Female
Gene Expression
Humans
Medulloblastoma
Mice
Mixed Function Oxygenases
Neovascularization, Pathologic
Protein Binding
Protein Transport
Radiation Tolerance
Radiation, Ionizing
Receptors, Urokinase Plasminogen Activator
Repressor Proteins
Tumor Burden
