Na,K-ATPase ?1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity.

ABSTRACT: 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 ?1-subunit has been associated with a poorly differentiated phenotype in carcinoma but its role in medulloblastoma progression is not known.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 ?1-subunit was knocked down in DAOY cells to test its role in medulloblastoma cell proliferation and tumorigenicity.Na,K-ATPase ?1-subunit levels increased with differentiation in normal CGP cells. Activation of Shh signaling resulted in reduced ?1-subunit mRNA and protein levels and was mimicked by overexpression of Gli1and Bmi1, both members of the Shh signaling cascade; overexpression of Bmi1 reduced ?1-subunit promoter activity. In human medulloblastoma cells, low ?1-subunit levels were associated with increased cell proliferation and in vivo tumorigenesis.Na,K-ATPase ?1-subunit is a target of the Shh signaling pathway and loss of ?1-subunit expression may contribute to tumor development and progression not only in carcinoma but also in medulloblastoma, a tumor of neuronal origin.

SUBMITTER: Lee SJ 

PROVIDER: S-EPMC4544806 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature