title: 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.
abstract: 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.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology and Pharmacology and Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, Illinois.
authors.forename: Swapna
authors.initials: S
authors.lastname: Asuthkar
authors.forename: Venkateswara Rao
authors.initials: VR
authors.lastname: Gogineni
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Velpula
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006899:Mixed Function Oxygenases; D055293:Receptors, Urokinase Plasminogen Activator; D012097:Repressor Proteins; C097341:helix-loop-helix protein, eHAND; C439790:HIF1AN protein, human