The Expression of Smads and Transforming Growth Factor Beta Receptors in Leiomyoma and Myometrium and the Effect of Gonadotropin Releasing Hormone Analogue Therapy

Gene microarray analysis indicated that several components of the transforming growth factor beta receptor (TGF-betaR) signaling pathway are differentially expressed in leiomyoma and myometrium. To validate the microarray results we evaluated the expression of Smads, intracellular proteins that transmit TGF-betaR signals, in leiomyoma and matched myometrium from untreated women, and women who received gonadotropin releasing hormone analogue (GnRHa) therapy. Semi-quantitative RT-PCR, Western blotting and immunohistochemistry indicate that leiomyoma and myometrium expresses receptor-activated Smad3, common Smad4 and inhibitory Smad7, with elevated expression of Smad3, Smad4 and phosphorylated Smad3 (pSmad3) as well as TGF-betaR type I and type II in leiomyoma compared to myometrium (P<0.05). GnRHa therapy resulted in lowering of TGF-betaRs as well as Smad4 and pSmad3, with concurrent increased in Smad7 expression in both leiomyoma and myometrium compared to untreated group (P<0.05). Immunohistochemically Smads and pSmad3 were localized in cytoplasmic/nuclear compartments of leiomyoma and myometrial smooth muscle cells and connective tissue fibroblasts, with alteration in their intensity (HScores) in GnRHa-treated group. In conclusion, the results indicates that leiomyoma and myometrium express all the components of TGF-betaR and Smads, and GnRHa therapy results in alteration of their expression further supporting the importance of TGF-beta system as key regulator of leiomyoma growth.