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Thymosin beta 4 gene silencing decreases stemness and invasiveness in glioblastoma

Hans-Georg Wirsching, Shanmugarajan Krishnan, Ana-Maria Florea, Karl Frei, Niklaus Krayenbühl, Kathy Hasenbach, Guido Reifenberger, Michael Weller, Ghazaleh Tabatabai
DOI: http://dx.doi.org/10.1093/brain/awt333 433-448 First published online: 19 December 2013

Summary

Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. Thymosin beta 4 gene silencing promotes differentiation of neural stem cells whereas thymosin beta 4 overexpression initiates cortical folding of developing brain hemispheres. A role of thymosin beta 4 in malignant gliomas has not yet been investigated. We analysed thymosin beta 4 staining on tissue microarrays and performed interrogations of the REMBRANDT and the Cancer Genome Atlas databases. We investigated thymosin beta 4 expression in seven established glioma cell lines and seven glioma-initiating cell lines and induced or silenced thymosin beta 4 expression by lentiviral transduction in LNT-229, U87MG and GS-2 cells to study the effects of altered thymosin beta 4 expression on gene expression, growth, clonogenicity, migration, invasion, self-renewal and differentiation capacity in vitro, and tumorigenicity in vivo. Thymosin beta 4 expression increased with grade of malignancy in gliomas. Thymosin beta 4 gene silencing in LNT-229 and U87MG glioma cells inhibited migration and invasion, promoted starvation-induced cell death in vitro and enhanced survival of glioma-bearing mice. Thymosin beta 4 gene silencing in GS-2 cells inhibited self-renewal and promoted differentiation in vitro and decreased tumorigenicity in vivo. Gene expression analysis suggested a thymosin beta 4-dependent regulation of mesenchymal signature genes and modulation of TGFβ and p53 signalling networks. We conclude that thymosin beta 4 should be explored as a novel molecular target for anti-glioma therapy.

  • glioblastoma
  • thymosin beta 4
  • invasion
  • stemness
  • Abbreviations
    MMP
    matrix metalloproteinase
    TB4
    thymosin beta 4
    TCGA
    The Cancer Genome Atlas
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