Loss of betaglycan expression in ovarian cancer: role in motility and invasion.
The transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta, activin, and inhibin, all have prominent roles in regulating normal ovarian function. Betaglycan, or the type III TGF-beta receptor, is a coreceptor that regulates TGF-beta, 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-beta-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.
Hempel
Nadine
N
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
How
Tam
T
Dong
Mei
M
Murphy
Susan K
SK
Fields
Timothy A
TA
Blobe
Gerard C
GC
D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007150:Immunohistochemistry; D007265:Inhibins / Q000378:metabolism; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071736:betaglycan; D007265:Inhibins; D008780:Methyltransferases