title: Modulation of the Wnt/beta-catenin pathway in human oligodendroglioma cells by Sox17 regulates proliferation and differentiation.
abstract: Oligodendrogliomas originate from oligodendrocyte progenitor cells (OPCs), whose development is regulated by the Sonic hedgehog and Wnt/beta-catenin pathways. We investigated the contribution of these pathways in the proliferation and differentiation of human oligodendroglioma cells (HOG). Inhibition of Hedgehog signaling with cyclopamine decreased cell survival and increased phosphorylated beta-catenin without altering myelin protein levels. Conversely, treatment of HOG with the Wnt antagonist secreted frizzled related protein (SFRP1), led to increased myelin protein levels and reduced cell proliferation, suggesting cell cycle arrest and differentiation. Unlike normal primary human OPCs, beta-catenin in HOG cells is not associated with endogenous Sox17 protein despite high levels of both proteins. Retroviral overexpression of recombinant Sox17 increased HOG cell cycle exit and apoptosis, and raised myelin protein levels and the percentage of O4(+) cells, indicating increased differentiation. Recombinant Sox17 also increased beta-catenin-TCF4-Sox17 complex formation and decreased total cellular levels of beta-catenin. These changes were associated with increased SFRP1, and reduced expression of Wnt-1 and Frizzled-1, -3 and -7 RNA, indicating that Sox17 induced a Hedgehog target, and regulated Wnt signaling at multiple levels. Our studies indicate that Wnt signaling regulates HOG cell cycle arrest and differentiation, and that recombinant Sox17 mediates modulation of the Wnt pathway through changes in beta-catenin, SFRP1 and Wnt/Frizzled expression. Our results thus identify Sox17 as a potential molecular target to include in HOG therapeutic strategies.
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Chew
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics; D000080865:Formins; D051157:Frizzled Receptors / Q000235:genetics; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology; D009185:Myelin Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D009837:Oligodendroglioma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger; D011994:Recombinant Proteins / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000378:metabolism*; D013234:Stem Cells; D014704:Veratrum Alkaloids / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D003598:Cytoskeletal Proteins; D000080865:Formins; D051157:Frizzled Receptors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009185:Myelin Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D055760:SOXF Transcription Factors; D014704:Veratrum Alkaloids; D051153:Wnt Proteins; D051176:beta Catenin; C476204:FMNL1 protein, human; C105574:FZD3 protein, human; C115810:FZD7 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109188:SOX17 protein, human; C000541:cyclopamine