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Semin Reprod Med 2004; 22(2): 83-90
DOI: 10.1055/s-2004-828614
Published 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Gene Expression Studies in Leiomyomata: New Directions for Research

William Catherino1 , Amal Salama1 , Clariss Potlog-Nahari1 , Phyllis Leppert1 , John Tsibris2 , James Segars1
  • 1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, and Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
  • 2Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida
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Publication History

Publication Date:
26 May 2004 (online)

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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.

KEYWORDS

Leiomyomata - microarray - extracellular matrix - molecular genetics - fibroids

REFERENCES

  • 1 Stewart E A. Uterine fibroids.  Lancet. 2001;  357 293-298
    CrossrefPubMedGoogle Scholar
  • 2 Gross K L, Morton C C. Genetics and the development of fibroids.  Clin Obstet Gynecol. 2001;  44 335-349
    CrossrefPubMedGoogle Scholar
  • 3 Myers E R, Barber M D, Gustilo-Ashby T, Couchman G, Matchar D B, McCroy D C. Management of uterine leiomyomata: what do we really know?.  Obstet Gynecol. 2002;  100 8-17
    CrossrefPubMedGoogle Scholar
  • 4 Forster T, Roy D, Ghazal P. Experiments using microarray technology: limitations and standard operating procedures.  J Endocrinol. 2003;  178 195-204
    CrossrefPubMedGoogle Scholar
  • 5 Tsibris J C, Segars J, Coppola D et al.. Insights from gene arrays on the development and growth regulation of uterine leiomyomata.  Fertil Steril. 2002;  78 1-8
    CrossrefPubMedGoogle Scholar
  • 6 Tsibris J CM, Maas S, Segars J et al.. New potential regulators of uterine leiomyomata from DNA arrays: the ionotropic glutamate receptor GluR2.  Biochem Biophys Res Commun. 2003;  312 249-254
    CrossrefPubMedGoogle Scholar
  • 7 Skubitz K, Skubitz A. Differential gene expression in uterine leiomyoma.  J Lab Clin Med. 2003;  141 297-308
    CrossrefPubMedGoogle Scholar
  • 8 Catherino W, Prupas C, Tsibris J et al.. Strategy for elucidating differentially expressed genes in leiomyoma identified by microarry technology.  Fertil Steril. 2003;  80 282-290
    PubMedGoogle Scholar
  • 9 Catherino W H, Leppert P C, Stenmark M et al.. Reduced dermatopontin expression is a molecular link between uterine leiomyomata and keloids.  Genes Chromosomes Cancer.. , In press
    PubMedGoogle Scholar
  • 10 Chegini N, Verala J, Luo X, Xu J, Williams R. Gene expression profile of leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy.  J Soc Gynecol Investig. 2003;  10 161-171
    CrossrefPubMedGoogle Scholar
  • 11 Wang H, Mahadevappa M, Yamamoto K et al.. Distinctive proliferative phase differences in gene expression in human myometrium and leiomyomata.  Fertil Steril. 2003;  80 266-276
    PubMedGoogle Scholar
  • 12 Christman G M, McCarthy J D. Gene therapy and uterine leiomyomas.  Clin Obstet Gynecol. 2001;  44 425-435
    CrossrefPubMedGoogle Scholar
  • 13 Spitz I M, Chwalisz K. Progesterone receptor modulators and progesterone antagonists in women's health.  Steroids. 2000;  65 807-815
    CrossrefPubMedGoogle Scholar
  • 14 Nowak R. Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.  Environ Health Perspect. 2000;  108 849-853
    PubMedGoogle Scholar
  • 15 Ligon A, Morton C. Leiomyomata: heritability and cytogenetic studies.  Hum Reprod Update. 2001;  7 8-14
    CrossrefPubMedGoogle Scholar
  • 16 Sato F, Mori M, Nishi M, Kudo R, Miyake H. Familial aggregation of uterine myomas in Japanese women.  J Epidemiol. 2002;  12 249-253
    CrossrefPubMedGoogle Scholar
  • 17 Marshall L, Spiegelman D, Barbieri R et al.. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race.  Obstet Gynecol. 1997;  90 967-973
    CrossrefPubMedGoogle Scholar
  • 18 Kashtan C E. Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes.  Medicine (Baltimore). 1999;  78 338-360
    CrossrefPubMedGoogle Scholar
  • 19 Sampson N S, Ryan S T, Enke D A, Cosgrove D, Koteliansky V, Gotwals P. Global gene expression analysis reveals a role for the α1 integrin in renal pathogenesis.  J Biol Chem. 2001;  276 34182-34188
    CrossrefPubMedGoogle Scholar
  • 20 Reed W B, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata.  Acta Derm Venereol. 1973;  53 409-416
    PubMedGoogle Scholar
  • 21 Martinez-Mir A, Gordon D, Horev L et al.. Multiple cutaneous and uterine leiomyomas: refinement of the genetic locus for multiple cutaneous and uterine leiomyomas on chromosome 1q42.3-43.  J Invest Dermatol. 2002;  118 876-880
    CrossrefPubMedGoogle Scholar
  • 22 Mitelman F, Mertens F, Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia.  Nat Genet. 1997;  15 417-474
    PubMedGoogle Scholar
  • 23 Dal Cin P, Quade B J, Neskey D M, Kleinman M S, Weremowicz S, Morton C. Intravenous leiomyomatosis is characterized by a der(14)t(12;14)(q15;q24).  Genes Chromosomes Cancer. 2003;  36 205-206
    CrossrefPubMedGoogle Scholar
  • 24 Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors.  Ann Chir Gynaecol. 1998;  87 278-281
    Google Scholar
  • 25 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
    CrossrefPubMedGoogle Scholar
  • 26 Freije W A. Genome biology and gynecology: the application of oligonucleotide microarrays to leiomyomata.  Fertil Steril. 2003;  80 277-278
    PubMedGoogle Scholar
  • 27 Walker C L. Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma.  Recent Prog Horm Res. 2002;  57 277-294
    CrossrefPubMedGoogle Scholar
  • 28 Tsibris J C, Porter K B, Jazayeri A et al.. Human uterine leiomyomata express higher levels of peroxisome proliferator-activated receptor γ, retinoid X receptor α, and all-trans retinoic acid than myometrium.  Cancer Res. 1999;  59 5737-5744
    PubMedGoogle Scholar
  • 29 Houston K D, Copland J A, Broaddus R R, Gottardis M M, Fischer S M, Walker C L. Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferators-activated receptor γ ligands in uterine leiomyoma.  Cancer Res. 2003;  63 1221-1227
    PubMedGoogle Scholar
  • 30 Nelson K G, Takahashi T, Bossert N L, Walmer D K, McLachlan J A. Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation.  Proc Natl Acad Sci U S A. 1991;  88 21-25
    PubMedGoogle Scholar
  • 31 Kalir T, Goldstein M, Dottino P et al.. Morphometric and electron-microscopic analyses of the effects of gonadotropin-releasing hormone agonists on uterine leiomyomas.  Arch Pathol Lab Med. 1998;  122 442-446
    PubMedGoogle Scholar
  • 32 Kresse H, Schönherr E. Proteoglycans of the extracellular matrix and growth control.  J Cell Physiol. 2001;  189 266-274
    CrossrefPubMedGoogle Scholar
  • 33 Iozzo R. The biology of small leucine-rich proteoglycans. Functional network of interactive proteins.  J Biol Chem. 1999;  274 18843-18846
    CrossrefPubMedGoogle Scholar
  • 34 Yamaguchi Y. Lecticans: organizers of the brain extracellular matrix.  Cell Mol Life Sci. 2000;  57 276-289
    PubMedGoogle Scholar
  • 35 Melrose J, Ghosh P, Taylor T. A comparative analysis of the differential spatial and temporal distributions of the large (aggrecan, versican) and small (decorin, biglycan, fibromodulin) proteoglycans of the intervertebral disc.  J Anat. 2001;  198 3-15
    CrossrefPubMedGoogle Scholar
  • 36 Soriano E S, Campos M, Michelacci Y M. Effect of epithelial debridement on glycosaminoglycan synthesis by human corneal explants.  Clin Chim Acta. 2000;  295 41-62
    CrossrefPubMedGoogle Scholar
  • 37 Berto A, Sampaio L, Franco C, Cesar Jr R, Michelacci Y. A comparative analysis of structure and spatial distribution of decorin in human leiomyoma and normal myometrium.  Biochim Biophys Acta. 2003;  1619 98-112
    PubMedGoogle Scholar
  • 38 Mehra A, Wrana J L. TGF-beta and the Smad signal transduction pathway.  Biochem Cell Biol. 2002;  80 605-622
    CrossrefPubMedGoogle Scholar
  • 39 Massague J, Wotton D. Transcriptional control by the TGF-β/Smad signaling system.  EMBO J. 2000;  19 1745-1754
    CrossrefPubMedGoogle Scholar
  • 40 Border W A, Noble N A. Transforming growth factor in tissue fibrosis.  N Engl J Med. 1994;  331 1286-1292
    CrossrefPubMedGoogle Scholar
  • 41 Lee B S, Nowak R A. Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta.  J Clin Endocrinol Metab. 2001;  86 913-920
    CrossrefPubMedGoogle Scholar
  • 42 Nowak R. Identification of new therapies for leiomyomas: what in vitro studies can tell us.  Clin Obstet Gynecol. 2001;  44 327-333
    CrossrefPubMedGoogle Scholar
  • 43 Arici A, Sozen I. Transforming growth factor-β3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation.  Fertil Steril. 2000;  73 1006-1011
    CrossrefPubMedGoogle Scholar
  • 44 Xu J, Luo X, Chegini N. Differential expression, regulation, and induction of smads, transforming growth factor-β signal transduction pathway in leiomyoma, and myometrial smooth muscle cells and alteration by gonadotropin-releasing hormone analog.  J Clin Endocrinol Metab. 2003;  88 1350-1361
    CrossrefPubMedGoogle Scholar
  • 45 Moustakas A, Souchelnytskyi S, Heldin C H. Smad regulation in TGF-β signal transduction.  J Cell Sci. 2001;  114 4359-4369
    PubMedGoogle Scholar
  • 46 Fukuhara K, Kariya M, Kita M et al.. Secreted frizzled related protein 1 is overexpressed in uterine leiomyomas, associated with a high estrogenic environment and unrelated to proliferative activity.  J Clin Endocrinol Metab. 2002;  87 1729-1736
    CrossrefPubMedGoogle Scholar
  • 47 Wong L L, Adler P N. Tissue polarity genes of Drosophila regulate the subcellular location for prehair pupal wing cells.  J Cell Biol. 1993;  123 209-221
    CrossrefPubMedGoogle Scholar
  • 48 Nakamura T, Sano M, Songyang Z, Schneider M D. A Wnt- and β-catenin-dependent pathway for mammalian cardiac myogenesis.  Proc Natl Acad Sci U S A. 2003;  100 5834-5839
    CrossrefPubMedGoogle Scholar
  • 49 Figarella-Branger D, Moreau H, Pellissier J F, Bianco N, Rougon G. CD24, a signal-transducing molecule expressed on human B lymphocytes, is a marker for human regenerating muscle.  Acta Neuropathol (Berl). 1993;  86 275-284
    CrossrefPubMedGoogle Scholar
  • 50 Kay R, Rosten P M, Humphries R K. CD24, a signal transducer modulating B cell activation responses, is a very short peptide with a glycosyl phosphatidylinositol membrane anchor.  J Immunol. 1991;  147 1412-1416
    PubMedGoogle Scholar
  • 51 Rougon G, Alterman L A, Dennis K, Guo X-J, Kinnon C. The murine heat-stable antigen: a differentiation antigen expressed in both the hematolymphoid and neural cell lineages.  Eur J Immunol. 1991;  21 1397-1402
    PubMedGoogle Scholar
  • 52 Jackson D, Waibel R, Weber E, Bell J, Stahel R A. CD24, a signal-transducing molecule expressed on human B cells, is a major surface antigen on small cell lung carcinomas.  Cancer Res. 1992;  52 5264-5270
    PubMedGoogle Scholar
  • 53 Walocha J A, Litwin J A, Miodonski A J. Vascular system of intramural leiomyomata revealed by corrosion casting and scanning electron microscopy.  Hum Reprod. 2003;  18 1088-1093
    CrossrefPubMedGoogle Scholar
  • 54 Gill S S, Pulido O M. Glutamate receptors in peripheral tissues: current knowledge, future research, and implications for toxicology.  Toxicol Pathol. 2001;  29 208-223
    PubMedGoogle Scholar

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