Betaglycan is a
type III TGFbeta receptor that modulates cellular sensitivity to
inhibins and
TGFbeta. Previous studies have suggested that
betaglycan acts as a
tumor suppressor in certain human epithelial
cancers. However, the roles of
betaglycan in ovarian
granulosa cell tumors (GCTs) are poorly understood. The objective of this study was to determine whether human GCTs exhibit
betaglycan expression and, if so, what impact this receptor has on
tumor biology. Real-time PCR was used to quantify
betaglycan transcripts in human GCTs (n = 17) and normal premenopausal ovaries (n = 11). This analysis established that GCTs exhibited a significant 2-fold lower mean
betaglycan mRNA level as compared with the normal ovary (P < 0.05). Similarly, two human GCT cell lines, KGN and COV434, exhibited low
betaglycan expression and poor responsiveness to
TGFbeta and
inhibin A in
luciferase reporter assays, which was restored by stable transfection of wild-type
betaglycan.
Betaglycan significantly increased the adhesion of COV434 (P < 0.05) and KGN (P < 0.0001) cells, decreased cellular invasion through
Matrigel, and inhibited wound healing. Expression of mutant forms of
betaglycan that are defective in
TGFbeta and/or
inhibin binding in each GCT cell line revealed that the inhibitory effects of
betaglycan on wound healing were most strongly linked to the
inhibin-binding region of
betaglycan. Furthermore, knockdown of INHA
mRNA expression abrogated the
betaglycan-mediated inhibition of wound healing and invasion, whereas both INHA silencing and
TGFbeta neutralization abolished the
betaglycan-mediated increase in adhesion to substrate. These data suggest that loss of
betaglycan contributes to the pathogenesis of GCTs.