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.
- SourceAvailable from: Beverley Vollenhoven
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- "Most studies that have examined differences between myometrium and fibroids using microarrays produced lists of approximately 100 genes that were differentially expressed between the two tissue types. An earlier review of five fibroid microarray studies (Catherino et al., 2004) reported only eight genes that were common in at least three out of five studies reviewed, with one study having no overlapping genes. A more recent review (Arslan et al., 2005) compared results of nine studies. "
ABSTRACT: Cultured myometrial (M) and fibroid (F) smooth muscle cells (SMCs) have been widely used as a model for the study of F growth. The aim of this study was to compare gene expression profiles using microarrays between six paired M and F tissues from hysterectomy specimens, as well as cells isolated from the same tissues and cultured for up to three passages. A total of 2055 genes were differentially expressed by ANOVA between all experimental groups. Among them, 128 genes were found to be statistically different between M and F tissues. More than 1100 genes were significantly changed between tissues and cultured cells, with 648 genes common between both M and F cells at P0 and P3. Expression profiles of six genes including estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) were also validated using real-time PCR. These data demonstrate that large changes occur in SMC gene expression in culture, reducing differences between M and F cells. They also show that ERalpha and PR levels are reduced in cells compared with whole tissue. These results indicate that although M and F cell cultures provide an important tool to study these tumours, in vitro studies must be carefully planned and evaluated to provide meaningful results.Molecular Human Reproduction 04/2006; 12(3):187-207. DOI:10.1093/molehr/gal018 · 3.48 Impact Factor
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ABSTRACT: To examine the ultrastructural characteristics of extracellular matrix and mature collagen fibrils in uterine leiomyomas and compare them with those in adjacent normal myometrium. Analysis of paired leiomyoma-myometrium in surgical specimens. Research center and tertiary care center. Women undergoing medically indicated hysterectomy for symptomatic uterine leiomyomas. None. Appearance and spatial orientation of the collagen fibrils in leiomyomas compared with myometrium. Observation of specimens at x 12,500 magnification indicated that collagen fibrils were more abundant, loosely packed, and arrayed in a nonparallel manner in leiomyomas compared with myometrium. Random areas were examined at x 6,500 to x 64,000 magnification and revealed collagen fibrils of equal diameter in both leiomyomas and myometrium. However, an ordered and regular barbed appearance was present in collagen fibrils from myometrium but was lacking in leiomyomas. Leiomyomas contain an abnormal collagen fibril structure and orientation, which suggests that the well-regulated fibril formation in myometrium is altered in leiomyomas. Alterations in collagen genes may play a role in the pathogenesis of leiomyomas.Fertility and Sterility 11/2004; 82 Suppl 3(supplement 3):1182-7. DOI:10.1016/j.fertnstert.2004.04.030 · 4.59 Impact Factor
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ABSTRACT: Uterine leiomyomas are extremely common and a major cause of pelvic pain, bleeding, infertility, and the leading indication for hysterectomy. Familial and epidemiological studies provide compelling evidence that genetic alterations play an important role in leiomyoma development. Using Affymetrix U133A GeneChip we analysed expression profiles of 22,283 genes in paired samples of leiomyoma and adjacent normal myometrium. We compared our results with previously published data on gene expression in uterine leiomyoma and identified the overlapping gene alterations. We detected 80 genes with average differences of > or = 2-fold and false discovery rates of < 5% (14 overexpressed and 66 underexpressed). A comparative analysis including eight previous gene expression studies revealed eight prominent genes (ADH1, ATF3, CRABP2, CYR61, DPT, GRIA2, IGF2, MEST) identified by at least five different studies, eleven genes (ALDH1, CD24, CTGF, DCX, DUSP1, FOS, GAGEC1, IGFBP6, PTGDS, PTGER3, TYMS) reported by four studies, twelve genes (ABCA, ANXA1, APM2, CCL21, CDKN1A, CRMP1, EMP1, ESR1, FY, MAP3K5, TGFBR2, TIMP3) identified by three studies, and 40 genes reported by two different studies. Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis, IGF metabolism, TGF-beta signaling and extracellular matrix formation. Gene expression studies provide clues to the relevant pathways of leiomyoma development.Human Reproduction 05/2005; 20(4):852-63. DOI:10.1093/humrep/deh698 · 4.59 Impact Factor