Na,K-ATPase β1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity
| Autor: | Sigrid A. Langhans, Sonali P. Barwe, Zhiqin Li, Seung Joon Lee, Alisa Litan, Stephan Lindsey, Bruce Graves |
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| Jazyk: | angličtina |
| Předmět: |
Cancer Research
Carcinogenesis medicine.disease_cause Zinc Finger Protein GLI1 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Cell Line Tumor medicine Humans Hedgehog Proteins RNA Messenger Sonic hedgehog Transcription factor Mitogen-Activated Protein Kinase 7 030304 developmental biology Cell Proliferation Medulloblastoma 0303 health sciences biology Cerebellar granule cell Research medicine.disease Hedgehog signaling pathway Gene Expression Regulation Neoplastic Brain tumor CXCL3 Ion homeostasis Oncology Na K-ATPase 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Signal transduction Sodium-Potassium-Exchanging ATPase Signal Transduction Transcription Factors |
| Zdroj: | Molecular Cancer |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/s12943-015-0430-1 |
| Popis: | Background The Sonic hedgehog (Shh) signaling pathway plays an important role in cerebellar development, and mutations leading to hyperactive Shh signaling have been associated with certain forms of medulloblastoma, a common form of pediatric brain cancer. While the fundamentals of this pathway are known, the molecular targets contributing to Shh-mediated proliferation and transformation are still poorly understood. Na,K-ATPase is a ubiquitous enzyme that maintains intracellular ion homeostasis and functions as a signaling scaffold and a cell adhesion molecule. Changes in Na,K-ATPase function and subunit expression have been reported in several cancers and loss of the β1-subunit has been associated with a poorly differentiated phenotype in carcinoma but its role in medulloblastoma progression is not known. Methods Human medulloblastoma cell lines and primary cultures of cerebellar granule cell precursors (CGP) were used to determine whether Shh regulates Na,K-ATPase expression. Smo/Smo medulloblastoma were used to assess the Na,K-ATPase levels in vivo. Na,K-ATPase β1-subunit was knocked down in DAOY cells to test its role in medulloblastoma cell proliferation and tumorigenicity. Results Na,K-ATPase β1-subunit levels increased with differentiation in normal CGP cells. Activation of Shh signaling resulted in reduced β1-subunit mRNA and protein levels and was mimicked by overexpression of Gli1and Bmi1, both members of the Shh signaling cascade; overexpression of Bmi1 reduced β1-subunit promoter activity. In human medulloblastoma cells, low β1-subunit levels were associated with increased cell proliferation and in vivo tumorigenesis. Conclusions Na,K-ATPase β1-subunit is a target of the Shh signaling pathway and loss of β1-subunit expression may contribute to tumor development and progression not only in carcinoma but also in medulloblastoma, a tumor of neuronal origin. |
| Databáze: | OpenAIRE |
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