title: Thymosin β 4 gene silencing decreases stemness and invasiveness in glioblastoma.
abstract: 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.
authors.affiliation: 1 Department of Neurology, Laboratory of Molecular Neuro-Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Wirsching
authors.forename: Shanmugarajan
authors.initials: S
authors.lastname: Krishnan
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Florea
authors.forename: Karl
authors.initials: K
authors.lastname: Frei
authors.forename: Niklaus
authors.initials: N
authors.lastname: Krayenbühl
authors.forename: Kathy
authors.initials: K
authors.lastname: Hasenbach
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D030541:Databases, Genetic; D005260:Female; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000502:physiology; D013947:Thymosin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D000099201:Thymosin beta(4)
chemical_list: D013947:Thymosin; D000099201:Thymosin beta(4)
keywords: glioblastoma; invasion; stemness; thymosin beta 4