title: Type III TGF-β receptor enhances colon cancer cell migration and anchorage-independent growth.
abstract: The type III TGF-β receptor (TβRIII or betagylcan) is a TGF-β superfamily coreceptor with emerging roles in regulating TGF-β superfamily signaling and cancer progression. Alterations in TGF-β superfamily signaling are common in colon cancer; however, the role of TβRIII has not been examined. Although TβRIII expression is frequently lost at the message and protein level in human cancers and suppresses cancer progression in these contexts, here we demonstrate that, in colon cancer, TβRIII messenger RNA expression is not significantly altered and TβRIII expression is more frequently increased at the protein level, suggesting a distinct role for TβRIII in colon cancer. Increasing TβRIII expression in colon cancer model systems enhanced ligand-mediated phosphorylation of p38 and the Smad proteins, while switching TGF-β and BMP-2 from inhibitors to stimulators of colon cancer cell proliferation, inhibiting ligand-induced p21 and p27 expression. In addition, increasing TβRIII expression increased ligand-stimulated anchorage-independent growth, a resistance to ligand- and chemotherapy-induced apoptosis, cell migration and modestly increased tumorigenicity in vivo. In a reciprocal manner, silencing endogenous TβRIII expression decreased colon cancer cell migration. These data support a model whereby TβRIII mediates TGF-β superfamily ligand-induced colon cancer progression and support a context-dependent role for TβRIII in regulating cancer progression.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Gatza
authors.forename: Alisha
authors.initials: A
authors.lastname: Holtzhausen
authors.forename: Kellye C
authors.initials: KC
authors.lastname: Kirkbride
authors.forename: Allyson
authors.initials: A
authors.lastname: Morton
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gatza
authors.forename: Michael B
authors.initials: MB
authors.lastname: Datto
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan