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Human Leiomyoma Smooth Muscle Cells Show Increased Expression of Transforming Growth Factor-ß3 (TGFß3) and Altered Responses to the Antiproliferative Effects of TGFß¹

Department of Obstetrics and Gynecology, Yong-Dong Severance Hospital (B.-S.L.), Seoul, Korea; and Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, and Brigham and Women’s Hospital (R.A.N.), Boston, Massachussets 02115

Address all correspondence and requests for reprints to: Dr. Romana A. Nowak, University of Illinois, 1207 West Gregory Drive, Urbana, Illinois 61801. E-mail: ranowak{at}uiuc.edu

Transforming growth factor-ßs (TGFßs) are multifunctional peptides that regulate growth and differentiation in a variety of cells. The goals of this study were to compare expression of the TGFß isoforms in normal myometrium and benign leiomyoma tumors of the uterus and to examine the effects of TGFßs on cell proliferation and collagen production by these cells in vitro. Myometrium and leiomyoma tissues were obtained from patients undergoing elective hysterectomies. Tissues were processed for ribonucleic acid (RNA) and were also established as primary cell cultures. Northern blot analysis showed that the levels of TGFß1 messenger RNAs (mRNAs) were similar between leiomyoma and myometrium, whereas leiomyoma showed 5-fold higher levels of expression of TGFß3 mRNA than autologous myometrium. Expression of TGFß3 protein detected by immunohistochemistry was much more intense in leiomyoma tissues than in corresponding myometrium. Levels of both TGFß1 and TGFß3 increased with increasing cell density for leiomyoma and myometrium smooth muscle cells cultured in vitro. Effects of TGFß1 and TGFß3 on cell proliferation were assessed by measuring changes in DNA synthesis with the tritiated thymidine incorporation assay. The doses of TGFßs tested were 0, 0.1, 1.0, and 10.0 ng/mL. All three doses of TGFß1 and TGFß3 inhibited DNA synthesis in myometrium smooth muscle cells by 31–54%. Concomitant treatment with an immunoneutralizing antibody to TGFß1–3 reversed this inhibitory effect. In contrast, TGFß1 had no effect on leiomyoma smooth muscle cells, whereas TGFß3 increased DNA synthesis by leiomyoma cells. Combined treatment with the immunoneutralizing antibody prevented this increase. Treatment of leiomyoma and myometrial cells with the TGFß immunoneutralizing antibody for 24 h caused a 45–60% reduction in collagen type I and type III mRNA levels, suggesting that endogenous TGFßs are important for collagen production. These results support the hypothesis that alterations in the TGFß system produce loss of sensitivity to the antiproliferative effects of TGFß, and increased expression of TGFß3 may contribute to the growth of these tumors.

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