Na,K-ATPase β1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity

Mol Cancer. 2015 Aug 19:14:159. doi: 10.1186/s12943-015-0430-1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / genetics*
  • Humans
  • Medulloblastoma / genetics*
  • Medulloblastoma / pathology
  • Mitogen-Activated Protein Kinase 7 / biosynthesis
  • RNA, Messenger / biosynthesis
  • Signal Transduction / genetics
  • Sodium-Potassium-Exchanging ATPase / biosynthesis*
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Transcription Factors / biosynthesis
  • Zinc Finger Protein GLI1

Substances

  • GLI1 protein, human
  • Hedgehog Proteins
  • RNA, Messenger
  • SHH protein, human
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7
  • Sodium-Potassium-Exchanging ATPase