Wnt3a mediated activation of Wnt/β-catenin signaling promotes tumor progression in glioblastoma

Mol Cell Neurosci. 2013 May;54:44-57. doi: 10.1016/j.mcn.2013.01.001. Epub 2013 Jan 19.

Abstract

Presence of a distinct population of cells that drives tumor progression supports the hierarchical model of tumor development in Glioblastoma (GBM) and substantiates the cancer stem cell hypothesis. Amongst the various developmental signaling pathways that are aberrantly activated, we here show that activated Wnt/β-catenin signaling pathway plays a critical role in malignant transformation and tumor progression in gliomas. We demonstrate that Wnt ligands - Wnt1 and Wnt3a are expressed in a graded manner in these tumors as well as over-expressed in glioma stem cell-lines. A selective inhibition of Wnt signaling pathway by selective knock-down of its ligands Wnt1 and Wnt3a in glioma-derived stem-like cells led to decreased cell proliferation, cell migration and chemo-resistance. Furthermore, Wnt silencing in glioma cells reduced the capacity to form intra-cranial tumors in vivo. Taken together, our study indicates Wnt/β-catenin signaling pathway as an essential driver of glioma tumorigenesis, recognizing role of Wnt3a as an oncogene and thereby offering novel therapeutic strategies for management of these tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / transplantation
  • Transcription, Genetic
  • Wnt Signaling Pathway*
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism*

Substances

  • WNT1 protein, human
  • WNT3A protein, human
  • Wnt1 Protein
  • Wnt3A Protein