This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, B.-S. Articles by Nowak, R. A. Search for Related Content PubMed PubMed Citation Articles by Lee, B.-S. Articles by Nowak, R. A.

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.

This article has been cited by other articles:

				P. S. Tanwar, H.-J. Lee, L. Zhang, L. R. Zukerberg, M. M. Taketo, B. R. Rueda, and J. M. Teixeira Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice Biol Reprod, September 1, 2009; 81(3): 545 - 552. [Abstract] [Full Text] [PDF]

				A. Morikawa, N. Ohara, Q. Xu, K. Nakabayashi, D. A. DeManno, K. Chwalisz, S. Yoshida, and T. Maruo Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer Hum. Reprod., April 1, 2008; 23(4): 944 - 951. [Abstract] [Full Text] [PDF]

				N. Ohara, A. Morikawa, Wei Chen, Jiayin Wang, D. A. DeManno, K. Chwalisz, and T. Maruo Comparative Effects of SPRM Asoprisnil (J867) on Proliferation, Apoptosis, and the Expression of Growth Factors in Cultured Uterine Leiomyoma Cells and Normal Myometrial Cells Reproductive Sciences, December 1, 2007; 14(8_suppl): 20 - 27. [Abstract] [PDF]

				H. Ishikawa, M. Shozu, M. Okada, M. Inukai, B. Zhang, K. Kato, T. Kasai, and M. Inoue Early growth response gene-1 plays a pivotal role in down-regulation of a cohort of genes in uterine leiomyoma J. Mol. Endocrinol., November 1, 2007; 39(5): 333 - 341. [Abstract] [Full Text] [PDF]

				N. J. Laping, J. I. Everitt, K. S. Frazier, M. Burgert, M. J. Portis, C. Cadacio, L. I. Gold, and C. L. Walker Tumor-Specific Efficacy of Transforming Growth Factor-{beta}RI Inhibition in Eker Rats Clin. Cancer Res., May 15, 2007; 13(10): 3087 - 3099. [Abstract] [Full Text] [PDF]

				Y. Zhao, Y. Wen, M. L. Polan, J. Qiao, and B. H. Chen Increased expression of latent TGF-{beta} binding protein-1 and fibrillin-1 in human uterine leiomyomata Mol. Hum. Reprod., May 1, 2007; 13(5): 343 - 349. [Abstract] [Full Text] [PDF]

				J. Wang, N. Ohara, Z. Wang, W. Chen, A. Morikawa, H. Sasaki, D. A. DeManno, K. Chwalisz, and T. Maruo A novel selective progesterone receptor modulator asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGFbeta3 and their receptors in cultured uterine leiomyoma cells Hum. Reprod., July 1, 2006; 21(7): 1869 - 1877. [Abstract] [Full Text] [PDF]

				X. Luo, E. Levens, R. S. Williams, and N. Chegini The expression of Abl interactor 2 in leiomyoma and myometrium and regulation by GnRH analogue and transforming growth factor-beta Hum. Reprod., June 1, 2006; 21(6): 1380 - 1386. [Abstract] [Full Text] [PDF]

				M. De Falco, S. Staibano, F. P. D'Armiento, M. Mascolo, G. Salvatore, A. Busiello, I. F. Carbone, F. Pollio, and A. Di Lieto Preoperative Treatment of Uterine Leiomyomas: Clinical Findings and Expression of Transforming Growth Factor-{beta}3 and Connective Tissue Growth Factor Reproductive Sciences, May 1, 2006; 13(4): 297 - 303. [Abstract] [PDF]

				X. Luo, L. Ding, and N. Chegini CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: inverse association with TGF-{beta} and regulation by TGF-{beta} in leiomyoma and myometrial smooth muscle cells Mol. Hum. Reprod., April 1, 2006; 12(4): 245 - 256. [Abstract] [Full Text] [PDF]

				C.J. Loy, S. Evelyn, F.K. Lim, M.H. Liu, and E.L. Yong Growth dynamics of human leiomyoma cells and inhibitory effects of the peroxisome proliferator-activated receptor-{gamma} ligand, pioglitazone Mol. Hum. Reprod., August 1, 2005; 11(8): 561 - 566. [Abstract] [Full Text] [PDF]

				E. Levens, X. Luo, L. Ding, R. S. Williams, and N. Chegini Fibromodulin is expressed in leiomyoma and myometrium and regulated by gonadotropin-releasing hormone analogue therapy and TGF-{beta} through Smad and MAPK-mediated signalling Mol. Hum. Reprod., July 1, 2005; 11(7): 489 - 494. [Abstract] [Full Text] [PDF]

				S.-J. Tsai, S.-J. Lin, Y.-M. Cheng, H.-M. Chen, and L.-Y. C. Wing Expression and Functional Analysis of Pituitary Tumor Transforming Growth Factor-1 in Uterine Leiomyomas J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3715 - 3723. [Abstract] [Full Text] [PDF]

				C.D. Swartz, C.A. Afshari, L. Yu, K.E. Hall, and D. Dixon Estrogen-induced changes in IGF-I, Myb family and MAP kinase pathway genes in human uterine leiomyoma and normal uterine smooth muscle cell lines Mol. Hum. Reprod., June 1, 2005; 11(6): 441 - 450. [Abstract] [Full Text] [PDF]

				A. A. Arslan, L. I. Gold, K. Mittal, T.-C. Suen, I. Belitskaya-Levy, M.-S. Tang, and P. Toniolo Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review Hum. Reprod., April 1, 2005; 20(4): 852 - 863. [Abstract] [Full Text] [PDF]

				X. Luo, L. Ding, J. Xu, and N. Chegini Gene Expression Profiling of Leiomyoma and Myometrial Smooth Muscle Cells in Response to Transforming Growth Factor-{beta} Endocrinology, March 1, 2005; 146(3): 1097 - 1118. [Abstract] [Full Text] [PDF]

				M. Shozu, K. Murakami, T. Segawa, T. Kasai, H. Ishikawa, K. Shinohara, M. Okada, and M. Inoue Decreased Expression of Early Growth Response-1 and Its Role in Uterine Leiomyoma Growth Cancer Res., July 1, 2004; 64(13): 4677 - 4684. [Abstract] [Full Text] [PDF]

				T. Maruo, N. Ohara, J. Wang, and H. Matsuo Sex steroidal regulation of uterine leiomyoma growth and apoptosis Hum. Reprod. Update, May 1, 2004; 10(3): 207 - 220. [Abstract] [Full Text] [PDF]

				N. Chegini, J. Verala, X. Luo, J. Xu, and R. S. Williams Gene Expression Profile of Leiomyoma and Myometrium and the Effect of Gonadotropin Releasing Hormone Analogue Therapy Reproductive Sciences, April 1, 2003; 10(3): 161 - 171. [Abstract] [PDF]

				J. Xu, X. Luo, and N. Chegini Differential Expression, Regulation, and Induction of Smads, Transforming Growth Factor-{beta} Signal Transduction Pathway in Leiomyoma, and Myometrial Smooth Muscle Cells and Alteration by Gonadotropin-Releasing Hormone Analog J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1350 - 1361. [Abstract] [Full Text] [PDF]

				H. Shime, M. Kariya, A. Orii, C. Momma, T. Kanamori, K. Fukuhara, T. Kusakari, Y. Tsuruta, K. Takakura, T. Nikaido, et al. Tranilast Inhibits the Proliferation of Uterine Leiomyoma Cells in Vitro through G1 Arrest Associated with the Induction of p21waf1 and p53 J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5610 - 5617. [Abstract] [Full Text] [PDF]

				N. Chegini, C. Ma, X.M. Tang, and R.S. Williams Effects of GnRH analogues, `add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-{beta} expression Mol. Hum. Reprod., December 1, 2002; 8(12): 1071 - 1078. [Abstract] [Full Text] [PDF]

				N. Danilovich, I. Roy, and M. R. Sairam Emergence of Uterine Pathology during Accelerated Biological Aging in FSH Receptor-Haploinsufficient Mice Endocrinology, September 1, 2002; 143(9): 3618 - 3627. [Abstract] [Full Text] [PDF]

				X. Wu, A. Blanck, G. Norstedt, L. Sahlin, and A. Flores-Morales Identification of genes with higher expression in human uterine leiomyomas than in the corresponding myometrium Mol. Hum. Reprod., March 1, 2002; 8(3): 246 - 254. [Abstract] [Full Text] [PDF]

				E. Levens, X. Luo, L. Ding, R. S. Williams, and N. Chegini Fibromodulin is expressed in leiomyoma and myometrium and regulated by gonadotropin-releasing hormone analogue therapy and TGF-{beta} through Smad and MAPK-mediated signalling Mol. Hum. Reprod., July 1, 2005; 11(7): 489 - 494. [Abstract] [Full Text] [PDF]