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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Medicine, 2 Obstetrics and Gynecology, 3 Pathology, and 4 Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina
Requests for reprints: Gerard C. Blobe, 221B MSRB Research Drive, Box 2631, Duke University Medical Center, Durham, NC 27710. Phone: 919-668-1352; Fax: 919-668-2458; E-mail: blobe001{at}mc.duke.edu.
The transforming growth factor-ß (TGF-ß) superfamily members, TGF-ß, activin, and inhibin, all have prominent roles in regulating normal ovarian function. Betaglycan, or the type III TGF-ß receptor, is a coreceptor that regulates TGF-ß, activin, and inhibin signaling. Here, we show that betaglycan expression is frequently decreased or lost in epithelial derived ovarian cancer at both the mRNA and protein level, with the degree of loss correlating with tumor grade. Treatment of ovarian cancer cell lines with the methyltransferase inhibitor 5-aza-2-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in significant synergistic induction of betaglycan message levels and increased betaglycan protein expression, indicating that epigenetic silencing may play a role in the loss of betaglycan expression observed in ovarian cancer. Although restoring betaglycan expression in Ovca429 ovarian cancer cells is not sufficient to restore TGF-ß–mediated inhibition of proliferation, betaglycan significantly inhibits ovarian cancer cell motility and invasiveness. Furthermore, betaglycan specifically enhances the antimigratory effects of inhibin and the ability of inhibin to repress matrix metalloproteinase levels in these cells. These results show, for the first time, epigenetic regulation of betaglycan expression in ovarian cancer, and a novel role for betaglycan in regulating ovarian cancer motility and invasiveness. [Cancer Res 2007;67(11):5231–8]
This article has been cited by other articles:
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  K. Mythreye and G. C. Blobe The type III TGF-{beta} receptor regulates epithelial and cancer cell migration through {beta}-arrestin2-mediated activation of Cdc42 PNAS, May 19, 2009; 106(20): 8221 - 8226. [Abstract] [Full Text] [PDF]
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 M. Bilandzic, S. Chu, P. G. Farnworth, C. Harrison, P. Nicholls, Y. Wang, R. M. Escalona, P. J. Fuller, J. K. Findlay, and K. L. Stenvers Loss of Betaglycan Contributes to the Malignant Properties of Human Granulosa Tumor Cells Mol. Endocrinol., April 1, 2009; 23(4): 539 - 548. [Abstract] [Full Text] [PDF]
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 K. J. Gordon, K. C. Kirkbride, T. How, and G. C. Blobe Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2 Carcinogenesis, February 1, 2009; 30(2): 238 - 248. [Abstract] [Full Text] [PDF]
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 E. C. Finger, N. Y. Lee, H.-j. You, and G. C. Blobe Endocytosis of the Type III Transforming Growth Factor-{beta} (TGF-{beta}) Receptor through the Clathrin-independent/Lipid Raft Pathway Regulates TGF-{beta} Signaling and Receptor Down-regulation J. Biol. Chem., December 12, 2008; 283(50): 34808 - 34818. [Abstract] [Full Text] [PDF]
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 T. L. Criswell, N. Dumont, J. V. Barnett, and C. L. Arteaga Knockdown of the Transforming Growth Factor-{beta} Type III Receptor Impairs Motility and Invasion of Metastatic Cancer Cells Cancer Res., September 15, 2008; 68(18): 7304 - 7312. [Abstract] [Full Text] [PDF]
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 V. Margulis, T. Maity, X.-Y. Zhang, S. J. Cooper, J. A. Copland, and C. G. Wood Type III Transforming Growth Factor-{beta} (TGF-{beta}) Receptor Mediates Apoptosis in Renal Cell Carcinoma Independent of the Canonical TGF-{beta} Signaling Pathway Clin. Cancer Res., September 15, 2008; 14(18): 5722 - 5730. [Abstract] [Full Text] [PDF]
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N. Hempel, T. How, S. J. Cooper, T. R. Green, M. Dong, J. A. Copland, C. G. Wood, and G. C. Blobe Expression of the type III TGF-{beta} receptor is negatively regulated by TGF-{beta} Carcinogenesis, May 1, 2008; 29(5): 905 - 912. [Abstract] [Full Text] [PDF]
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K. C. Kirkbride, T. A. Townsend, M. W. Bruinsma, J. V. Barnett, and G. C. Blobe Bone Morphogenetic Proteins Signal through the Transforming Growth Factor-{beta} Type III Receptor J. Biol. Chem., March 21, 2008; 283(12): 7628 - 7637. [Abstract] [Full Text] [PDF]
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E. C. Finger, R. S. Turley, M. Dong, T. How, T. A. Fields, and G. C. Blobe T{beta}RIII suppresses non-small cell lung cancer invasiveness and tumorigenicity Carcinogenesis, March 1, 2008; 29(3): 528 - 535. [Abstract] [Full Text] [PDF]
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K. J. Gordon, M. Dong, E. M. Chislock, T. A. Fields, and G. C. Blobe Loss of type III transforming growth factor {beta} receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression Carcinogenesis, February 1, 2008; 29(2): 252 - 262. [Abstract] [Full Text] [PDF]
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H. J. You, M. W. Bruinsma, T. How, J. H. Ostrander, and G. C. Blobe The type III TGF- receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation Carcinogenesis, December 1, 2007; 28(12): 2491 - 2500. [Abstract] [Full Text] [PDF]
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