Abstract
Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ≥ 1.5 fold, P ≤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 µg/ml) in UtLM cells. Downregulation of TGF-β signaling pathway genes, activin A, activin B, Smad3, TGF-β2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-β pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas.
Highlights
Uterine leiomyomas are the leading indication for hysterectomy in the United States with the estimated cumulative incidence of tumors by age 50 being > 80% for black women and nearly 70% for white women in the United States (Walker and Stewart, 2005; Viswanathan et al, 2007)
We found that the protein expression of both activin A and Smad3 was decreased in genistein-treated uterine leiomyoma (UtLM) cells compared to vehicletreated (Figure 2), suggesting that the decreased protein expression of activin A and Smad3 might due to the down-regulation of INHBA and Smad3 genes, possibly leading to the inhibitory effects of genistein on UtLM cells
The purpose of the present study was to identify the novel pathways and genes that might be involved in the inhibitory effect of a high dose of genistein on UtLM cells
Summary
Uterine leiomyomas (i.e., fibroids, myomas) are the leading indication for hysterectomy in the United States with the estimated cumulative incidence of tumors by age 50 being > 80% for black women and nearly 70% for white women in the United States (Walker and Stewart, 2005; Viswanathan et al, 2007) These tumors represent a tremendous public health burden and economic cost to society. Surgical intervention is still the standard and most effective treatment for uterine leiomyomas (Rackow and Arici, 2006; Tulandi, 2007) Therapeutic agents, such as gonadotropin-releasing hormone (GnRH) agonists are being used clinically (Chegini et al, 2002), and selective estrogen-receptor modulators (SERMs) (Liu et al, 2007), selective progesterone-receptor modulators (SPRMs)
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