Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm289
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TβRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity
1 Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710
2 Duke University Medical Center, Department of Medicine, Durham, NC 27710
3 Duke University Medical Center, Department of Pathology, Durham, NC 27710
4 Corresponding author: 221B MSRB Research Drive, Box 2631 DUMC, Durham, NC 27710, Tel: (919) 668-1352, Fax: (919) 668-2458, Email: blobe001{at}mc.duke.edu
The transforming growth factor-β (TGF-β) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. While most lung cancers become resistant to the tumor suppressor effects of TGF-β, and loss or mutation of one of the components of the TGF-β signaling pathway, including TβRII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII, or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased TβRIII expression, suggesting LOH as one mechanism for TβRIII loss. In the H460 cell model of NSCLC, restoring TβRIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring TβRIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-β1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA mediated silencing of endogenous TβRIII expression enhanced invasion through Matrigel. Mechanistically, TβRIII functions, at least in part, through undergoing ectodomain shedding, generating soluble TβRIII, which is able to inhibit cellular invasiveness. Taken together, these results support TβRIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorage-independent growth of lung cancer cells.
Key Words: tumor suppressor • TGF-β signaling • lung cancer • invasion • tumorigenesis
* These authors contributed equally to this work
Received August 21, 2007; revised October 29, 2007; accepted December 7, 2007.
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