Abstract
Abstract Urokinase-type plasminogen activator (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. Most recently, 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 this study, we show that the uPAR protein is a cytoplasmic sequestration factor for a novel basic helix-loop-helix (bHLH) transcription factor, Hand-1. The Hand-1 protein plays an essential role in differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contributions to cancer remain mostly unknown. In the present study, we observed that Hand-1 protein is upregulated in uPAR shRNA-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, such as HIF-1 alpha. 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. Citation Format: Swapna Asuthkar, Kiran Kumar Velpula, Arun Kumar Nalla, Venkateswara Rao Gogineni, Venkata Ramesh Dasari, Bharathi Gorantla, Jasti S. Rao. uPAR-regulated nuclear translocation of hand-1 mediates vascular radiosensitivity in medulloblastoma tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2013-3904
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