Mol. Hum. Reprod. Advance Access originally published online on March 29, 2006
Molecular Human Reproduction 2006 12(4):245-256; doi:10.1093/molehr/gal015
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CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: inverse association with TGF-ß and regulation by TGF-ß in leiomyoma and myometrial smooth muscle cells
Department of Obstetrics and Gynecology, University of Florida, Gainesville, FL, USA
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Florida, Box 100294, Gainesville, FL 32610, USA. E-mail: cheginin{at}obgyn.ufl.edu
Connective tissue growth factor (CTGF; CCN2) is considered to serve as downstream midiator of TGF-ß action in tissue fibrosis. We tested this hypothesis in paired leiomyoma and myometrium by evaluating the expression of TGF-ß1/TGF-ß3 and CCN2, the other members of the CCN family, CCN3 and CCN4, as well as fibulin-1C and S100A4, calcium-binding proteins that interact with CCNs. The regulatory function of TGF-ß1 on the expression of these genes was further evaluated using leiomyoma (L) and myometrial (M) smooth muscle cells (SMC). Real-time PCR, Western blotting and immunohistochemistry revealed that leiomyomas and myometrium express CCNs, fibulin-1C and S100A4, whose levels of expression with the exception of fibulin-1C were lower in leiomyomas and inversely correlated with the expression of TGF-ß1 and TGF-ß3 (P<0.05). The expression of these genes was menstrual cycle-independent and GnRHa therapy increased the expression of CCN2 in leiomyomas, while inhibiting CCN3, CCN4 and S100A4 in myometrium (P<0.05). TGF-ß (2.5 ng/ml) in a time- and cell-dependent manner, and through MAPK and Smad pathways, differentially regulated the expression of these genes in LSMC and MSMC. We concluded that CCNs, fibulin-1C and S100A4 are expressed in leiomyomas/myometrium with relative expression levels inversely correlating with TGF-ßs and influenced by GnRHa and TGF-ß regulatory actions. The results suggest that unlike other fibrotic disorders, CCN2 (CTGF), at least at tissue level, may not serve as a downstream mediator of TGF-ß action in leiomyomas.
Key words: CCNs/expression/fibulin/S100A4/TGF-ß
Presented in part at the 52nd annual meeting of the Society for Gynecological Investigation, Los Angles, CA, March 2005.
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