期刊
MOLECULAR CANCER THERAPEUTICS
卷 16, 期 6, 页码 1177-1186出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0465
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- Isarna (Munich, Germany)
- Swiss Cancer League/Oncosuisse [KFS-3305-08-2013]
- Canton of Zurich [HSM-2]
Transforming growth factor (TGF)-beta contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-beta(1) and TGF-beta(2) isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-beta(3) in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-beta(3) in glioblastoma models. TGF-beta(3) mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-beta(1) or TGF-beta(2) in most cell lines. Inhibition of TGF-beta(3) mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-beta(1) or TGF-beta(2) mRNA expression or protein levels. Moreover, inhibition of TGF-beta(3) expression reduces invasiveness in vitro. Interestingly, depletion of TGF-beta(3) also attenuates signaling evoked by TGF-beta(1) or TGF-beta(2). In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-beta(3) as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-beta(1) and TGF-beta(2) levels were unaffected following systemic treatment with TGF-beta(3)- specific antisense oligonucleotides. We conclude that TGF-beta(3) might function as a gatekeeper controlling downstream signaling despite high expression of TGF-beta(1) and TGF-beta(2) isoforms. Targeting TGF-beta(3) in vivo may represent a promising strategy interfering with aberrant TGF-beta signaling in glioblastoma. (C) 2017 AACR.
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