Gene expression studies in leiomyomata: new directions for research.
ABSTRACT Uterine leiomyomata (fibroids) are a leading women's health problem, resulting in significant morbidity and surgical intervention. As benign clonal tumors, leiomyomata also represent a target well suited to molecular analysis. Familial studies and genetic syndromes featuring leiomyomata provide compelling evidence that genetic alterations may cause fibroid development, but the specific genes involved in leiomyoma development have not been identified. Microarrays permit simultaneous comparison of the relative expression of thousands of genes, thereby highlighting specific genes that may play a role in the development of leiomyomata. Microarray studies conducted by several laboratories have identified candidate genes. However, few gene products have been confirmed with alternative experimental approaches. The objective of this article is to focus on the insights provided by microarray studies investigating leiomyoma development. Such studies suggest that although hormonal control of leiomyoma growth is observed, there are other critical pathways involved in development of the leiomyoma cell phenotype that warrant investigation. In particular, expression of extracellular matrix genes in leiomyomata is deranged and such genes represent potential novel targets for therapy.
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ABSTRACT: To investigate the impact of liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system. Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture. Laboratory study. None. Treatment of leiomyoma and myometrial cells with liarozole and TGF-β3 in a three-dimensional culture system. Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blotting to assess fold gene and protein expression of TGF-β3 and TGF-β3 regulated fibrotic cytokines: collagen 1A1 (COL1A1), fibronectin, and versican before and after treatment with liarozole, and confirmatory immunohistochemical stains of treated three-dimensional cultures. Both TGF-β3 gene and protein expression were elevated in leiomyoma cells compared with myometrium in two-dimensional and 3D cultures. Treatment with liarozole decreased TGF-β3 gene and protein expression. Extracellular matrix components versican, COL1A1, and fibronectin were also decreased by liarozole treatment in 3D cultures. Treatment of 3D cultures with TGF-β3 increased gene expression and protein production of COL1A1, fibronectin, and versican. Liarozole decreased TGF-β3 and TGF-β3-mediated extracellular matrix expression in a 3D uterine leiomyoma culture system.Fertility and sterility 05/2014; 102(1). DOI:10.1016/j.fertnstert.2014.03.042 · 4.30 Impact Factor
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ABSTRACT: To describe alterations of gene expression patterns of the alcohol dehydrogenase-1 (ADH1) gene in human leiomyoma tissue. We correlated changes in ADH1 gene activity with several clinical and demographic variables. We compared gene expression patterns of ADH1 in leiomyoma tissue samples obtained from 101 hysterectomy cases to 110 cases of hysterectomy performed for non-oncological indications. Gene expression was determined by standard PCR technique. Clinical and epidemiological data were extracted from the computerized database of the 1st Department of Obstetrics and Gynecology of Semmelweis University and from patient questionnaires. Median age in the leiomyoma group was significantly lower than in the control group (47.5±12.1 vs. 54.7±10.2 years). The incidence of uterine leiomyoma was highest (48%) in the 41-50 year age group. In the obstetric history, cumulative gestational age in the leiomyoma group was significantly lower (105.1±8.2 weeks) than in the control group (127.2±9.1 weeks) and cumulative lactation length was also significantly shorter (2.4±1.2 months vs. 5.1±2.2 months). Surgical treatment of the fibroid was myomectomy in 39.6% of the cases and hysterectomy in 60.4%. The ADH1 gene was significantly underexpressed in the leiomyoma group compared to the control group. There was no significant association between ADH1 gene expression and family history. Within the leiomyoma group, there was no significant difference in ADH1 gene expression between subgroups of cases with different number of fibroid tumors found in the hysterectomy sample, but individual tumor number did correlate with the degree of underexpression of the ADH1 gene. There was no significant association between ADH1 gene expression and cumulative history of lactation. Underexpression of the ADH1 gene, which influences the transformation of the extracellular matrix, plays a probable role in the etiology of uterine fibroid. Although significant differences in ADH1 gene activity were not seen, a negative correlation between tumor number and degree of ADH1 underexpression was found. Neither family history nor cumulative lactation length was a significant predictor of uterine leiomyoma.European journal of obstetrics, gynecology, and reproductive biology 07/2013; 170(2). DOI:10.1016/j.ejogrb.2013.07.007 · 1.63 Impact Factor
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ABSTRACT: Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.International Journal of Women's Health 01/2014; 6:95-114. DOI:10.2147/IJWH.S51083