Semin Reprod Med 2008; 26(6): 500-514
DOI: 10.1055/s-0028-1096130
© Thieme Medical Publishers

The Expression and Potential Regulatory Function of MicroRNAs in the Pathogenesis of Leiomyoma

Xiaoping Luo1 , 3 , Nasser Chegini2 , 3
  • 1Research Assistant Professor
  • 2Professor
  • 3Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida
Further Information

Publication History

Publication Date:
24 October 2008 (online)

ABSTRACT

Leiomyomas are benign uterine tumors considered to arise from transformation of myometrial cells. What initiates the conversion of myometrial cells into leiomyoma is unknown, however cytogenetic analysis often shows occurrence of nonrandom chromosomal abnormalities that may account for their establishment. It is clear that ovarian steroids are essential for leiomyoma growth, and local expression of many autocrine/paracrine mediators serving as key regulators of cell-cycle progression, cellular hypertrophy, extracellular matrix accumulation, and apoptosis appear to play central roles in this capacity. However, the stability of the expression of these genes represents the hallmarks of leiomyoma establishment, growth, and regression. With the emergence of microRNA (miRNA) as a key regulator of gene expression stability, in this review we present evidence for the expression and potential regulatory functions on miRNAs in leiomyoma with particular emphasis on the expression of their selective target genes whose products influence various cellular activities critical to pathogenesis of leiomyomas.

REFERENCES

  • 1 Parker W H. Etiology, symptomatology, and diagnosis of uterine myomas.  Fertil Steril. 2007;  87 725-736
  • 2 Wise L A, Palmer J R, Stewart E A et al.. Age-specific incidence rates for self-reported uterine leiomyomata in the Black Women's Health Study.  Obstet Gynecol. 2005;  105 563-568
  • 3 Al Hendy A, Salama S A. Catechol-O-methyltransferase polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups.  J Soc Gynecol Investig. 2006;  13 136-144
  • 4 Denschlag D, Bentz E K, Hefler L et al.. Genotype distribution of estrogen receptor-alpha, catechol-O-methyltransferase, and cytochrome P450 17 gene polymorphisms in Caucasian women with uterine leiomyomas.  Fertil Steril. 2006;  85 462-467
  • 5 Villanova F E, Andrade P M, Otsuka A Y et al.. Estrogen receptor alpha polymorphism and susceptibility to uterine leiomyoma.  Steroids. 2006;  71 960-965
  • 6 Lobel M K, Somasundaram P, Morton C C. The genetic heterogeneity of uterine leiomyomata.  Obstet Gynecol Clin North Am. 2006;  33 13-39
  • 7 Luo X, Ding L, Xu J et al.. Leiomyoma and myometrial gene expression profiles and their responses to gonadotropin-releasing hormone analog therapy.  Endocrinology. 2005;  146 1074-1096
  • 8 Luo X, Ding L, Xu J et al.. Gene expression profiling of leiomyoma and myometrial smooth muscle cells in response to transforming growth factor-beta.  Endocrinology. 2005;  146 1097-1118
  • 9 Quade B J, Wang T Y, Sornberger K et al.. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling.  Genes Chromosomes Cancer. 2004;  40 97-108
  • 10 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;  78 114-121
  • 11 Pan Q, Luo X, Chegini N. Genomic and proteomic profiling I: leiomyomas in African Americans and Caucasians.  Reprod Biol Endocrinol. 2007;  5 34
  • 12 Bartel D P. MicroRNAs: genomics, biogenesis, mechanism, and function.  Cell. 2004;  116 281-297
  • 13 Calin G A, Croce C M. MicroRNA signatures in human cancers.  Nat Rev Cancer. 2006;  6 857-866
  • 14 Calin G A, Croce C M. MicroRNAs and chromosomal abnormalities in cancer cells.  Oncogene. 2006;  25 6202-6210
  • 15 Engels B M, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation.  Oncogene. 2006;  25 6163-6169
  • 16 Jovanovic M, Hengartner M O. miRNAs and apoptosis: RNAs to die for.  Oncogene. 2006;  25 6176-6187
  • 17 Zeng Y. Principles of micro-RNA production and maturation.  Oncogene. 2006;  25 6156-6162
  • 18 Calin G A, Pekarsky Y, Croce C M. The role of microRNA and other non-coding RNA in the pathogenesis of chronic lymphocytic leukemia.  Best Pract Res Clin Haematol. 2007;  20 425-437
  • 19 Ku G, McManus M T. Behind the scenes of a small RNA gene-silencing pathway.  Hum Gene Ther. 2008;  19 17-26
  • 20 Mineno J, Okamoto S, Ando T et al.. The expression profile of microRNAs in mouse embryos.  Nucleic Acids Res. 2006;  34 1765-1771
  • 21 Morita S, Horii T, Kimura M et al.. One Argonaute family member, Eif2c2 (Ago2), is essential for development and appears not to be involved in DNA methylation.  Genomics. 2007;  89 687-696
  • 22 Murchison E P, Stein P, Xuan Z et al.. Critical roles for Dicer in the female germline.  Genes Dev. 2007;  21 682-693
  • 23 O'Carroll D, Mecklenbrauker I, Das P P et al.. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway.  Genes Dev. 2007;  21 1999-2004
  • 24 Yu Z, Jian Z, Shen S H et al.. Global analysis of microRNA target gene expression reveals that miRNA targets are lower expressed in mature mouse and Drosophila tissues than in the embryos.  Nucleic Acids Res. 2007;  35 152-164
  • 25 Roldo C, Missiaglia E, Hagan J P et al.. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior.  J Clin Oncol. 2006;  24 4677-4684
  • 26 Zhao J J, Hua Y J, Sun D G et al.. Genome-wide microRNA profiling in human fetal nervous tissues by oligonucleotide microarray.  Childs Nerv Syst. 2006;  22 1419-1425
  • 27 Volinia S, Calin G A, Liu C G et al.. A microRNA expression signature of human solid tumors defines cancer gene targets.  Proc Natl Acad Sci U S A. 2006;  103 2257-2261
  • 28 Marsh E E, Lin Z, Yin P et al.. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium.  Fertil Steril. 2008;  89 1771-1776
  • 29 Pan Q, Luo X, Chegini N. Differential expression of microRNAs in myometrium and leiomyomas and regulation by ovarian steroids.  J Cell Mol Med. 2008;  12 227-240
  • 30 Wang T, Zhang X, Obijuru L et al.. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas.  Genes Chromosomes Cancer. 2007;  46 336-347
  • 31 Brennecke J, Stark A, Russell R B et al.. Principles of microRNA-target recognition.  PLoS Biol. 2005;  3 e85
  • 32 Grimson A, Farh K K, Johnston W K et al.. MicroRNA targeting specificity in mammals: determinants beyond seed pairing.  Mol Cell. 2007;  27 91-105
  • 33 Belge G, Meyer A, Klemke M et al.. Upregulation of HMGA2 in thyroid carcinomas: a novel molecular marker to distinguish between benign and malignant follicular neoplasias.  Genes Chromosomes Cancer. 2008;  47 56-63
  • 34 Pan Q, Luo X, Chegini N. Regulation and function analysis of mir-21 in leiomyoma and myometrium smooth muscle cells as well as in transformed leiomyoma and leiomyosarcoma cells.  Reprod Sci. 2008;  15 158A
  • 35 Gauldie J, Bonniaud P, Sime P et al.. TGF-beta, Smad3 and the process of progressive fibrosis.  Biochem Soc Trans. 2007;  35 661-664
  • 36 Rahimi R A, Leof E B. TGF-beta signaling: a tale of two responses.  J Cell Biochem. 2007;  102 593-608
  • 37 Schmierer B, Hill C S. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.  Nat Rev Mol Cell Biol. 2007;  8 970-982
  • 38 Chegini N. Gene expression and hormonal response. In: Brosens I Uterine Leiomyomata: Pathogenesis and Management. London, UK; Taylor & Francis 2005: 41-67
  • 39 Jenkins G. The role of proteases in transforming growth factor-beta activation.  Int J Biochem Cell Biol. 2008;  40 1068-1078
  • 40 Leask A. Targeting the TGFbeta, endothelin-1 and CCN2 axis to combat fibrosis in scleroderma.  Cell Signal. 2008;  40 1068-1078
  • 41 Cho W C. OncomiRs: the discovery and progress of microRNAs in cancers.  Mol Cancer. 2007;  6 60
  • 42 Cimmino A, Calin G A, Fabbri M et al.. miR-15 and miR-16 induce apoptosis by targeting BCL2.  Proc Natl Acad Sci U S A. 2005;  102 13944-13949
  • 43 He L, He X, Lowe S W et al.. microRNAs join the p53 network—another piece in the tumour-suppression puzzle.  Nat Rev Cancer. 2007;  7 819-822
  • 44 He X, He L, Hannon G J. The guardian's little helper: microRNAs in the p53 tumor suppressor network.  Cancer Res. 2007;  67 11099-11101
  • 45 Sales K M, Winslet M C, Seifalian A M. Stem cells and cancer: an overview.  Stem Cell Rev. 2007;  3 249-255
  • 46 Foshay K M, Gallicano G I. Small RNAs, big potential: the role of microRNAs in stem cell function.  Curr Stem Cell Res Ther. 2007;  2 264-271
  • 47 Togel F, Westenfelder C. Adult bone marrow-derived stem cells for organ regeneration and repair.  Dev Dyn. 2007;  236 3321-3331
  • 48 Mori A, Nakayama K, Suzuki J et al.. Analysis of stem cell factor for mast cell proliferation in the human myometrium.  Mol Hum Reprod. 1997;  3 411-418
  • 49 Lakshmipathy U, Hart R P. Concise review: microRNA expression in multipotent mesenchymal stromal cells.  Stem Cells. 2008;  26 356-363
  • 50 Ahn W S, Kim K W, Bae S M et al.. Targeted cellular process profiling approach for uterine leiomyoma using cDNA microarray, proteomics and gene ontology analysis.  Int J Exp Pathol. 2003;  84 267-279
  • 51 Wei J J, Chiriboga L, Arslan A A et al.. Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata.  Hum Reprod. 2006;  21 57-67
  • 52 Chwalisz K, Perez M C, Demanno D et al.. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.  Endocr Rev. 2005;  26 423-438
  • 53 Levens E D, Potlog-Nahari C, Armstrong A Y et al.. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.  Obstet Gynecol. 2008;  111 1129-1136
  • 54 Chegini N, Ma C, Tang X M et al.. 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. 2002;  8 1071-1078
  • 55 Xu Q, Ohara N, Chen W et al.. Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells.  Hum Reprod. 2006;  21 2408-2416
  • 56 Ohara N, Morikawa A, Chen W et al.. Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells.  Reprod Sci. 2007;  14 20-27
  • 57 Al Hendy A, Salama S. Gene therapy and uterine leiomyoma: a review.  Hum Reprod Update. 2006;  12 385-400
  • 58 Chegini N. Implication of growth factor and cytokine networks in leiomyomas. In: Hill J Cytokines in Human Reproduction. New York, NY; John Wiley & Sons 2000: 133-159
  • 59 Walker C L, Stewart E A. Uterine fibroids: the elephant in the room.  Science. 2005;  308 1589-1592
  • 60 Catherino W, Salama A, Potlog-Nahari C et al.. Gene expression studies in leiomyomata: new directions for research.  Semin Reprod Med. 2004;  22 83-90
  • 61 Nowak R A. Identification of new therapies for leiomyomas: what in vitro studies can tell us.  Clin Obstet Gynecol. 2001;  44 327-334
  • 62 Andersen J. Factors in fibroid growth.  Baillieres Clin Obstet Gynaecol. 1998;  12 225-243
  • 63 Kawaguchi K, Fujii S, Konishi I et al.. Mitotic activity in uterine leiomyomas during the menstrual cycle.  Am J Obstet Gynecol. 1989;  160 637-641
  • 64 Martel K M, Ko A C, Christman G M et al.. Apoptosis in human uterine leiomyomas.  Semin Reprod Med. 2004;  22 91-103
  • 65 Maruo T, Ohara N, Wang J et al.. Sex steroidal regulation of uterine leiomyoma growth and apoptosis.  Hum Reprod Update. 2004;  10 207-220
  • 66 Chegini N. Peritoneal molecular environment, adhesion formation and clinical implication.  Front Biosci. 2002;  7 e91-e115
  • 67 Sylvestre Y, De Guire V, Querido E et al.. An E2F/miR-20a autoregulatory feedback loop.  J Biol Chem. 2007;  282 2135-2143
  • 68 Diederichs S, Haber D A. Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing.  Cancer Res. 2006;  66 6097-6104
  • 69 Meng F, Henson R, Lang M et al.. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.  Gastroenterology. 2006;  130 2113-2129
  • 70 Si M L, Zhu S, Wu H et al.. miR-21-mediated tumor growth.  Oncogene. 2007;  26 2799-2803
  • 71 Naguibneva I, Ameyar-Zazoua M, Polesskaya A et al.. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation.  Nat Cell Biol. 2006;  8 278-284
  • 72 Adams B D, Furneaux H, White B A. The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines.  Mol Endocrinol. 2007;  21 1132-1147
  • 73 Visone R, Pallante P, Vecchione A et al.. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.  Oncogene. 2007;  26 7590-7595
  • 74 Berlingieri M T, Pierantoni G M, Giancotti V et al.. Thyroid cell transformation requires the expression of the HMGA1 proteins.  Oncogene. 2002;  21 2971-2980
  • 75 Wong C F, Tellam R L. microRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis.  J Biol Chem. 2008;  283 9836-9843
  • 76 Tsuchiya Y, Nakajima M, Takagi S et al.. MicroRNA regulates the expression of human cytochrome P450 1B1.  Cancer Res. 2006;  66 9090-9098
  • 77 Mertens-Talcott S U, Chintharlapalli S, Li X et al.. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells.  Cancer Res. 2007;  67 11001-11011
  • 78 Johnson C D, Esquela-Kerscher A, Stefani G et al.. The let-7 microRNA represses cell proliferation pathways in human cells.  Cancer Res. 2007;  67 7713-7722
  • 79 Luo X, Pan Q, Liu L et al.. Genomic and proteomic profiling II: comparative assessment of gene expression profiles in leiomyomas, keloids, and surgically-induced scars.  Reprod Biol Endocrinol. 2007;  5 35
  • 80 Tatsuguchi M, Seok H Y, Callis T E et al.. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy.  J Mol Cell Cardiol. 2007;  42 1137-1141
  • 81 Ji R, Cheng Y, Yue J et al.. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation.  Circ Res. 2007;  100 1579-1588
  • 82 Sayed D, Hong C, Chen I Y et al.. MicroRNAs play an essential role in the development of cardiac hypertrophy.  Circ Res. 2007;  100 416-424
  • 83 Chegini N. TGF-b System: the principal pro-fibrotic mediator of peritoneal adhesion formation.  Semin Reprod Med. 2008;  26 298-312
  • 84 Hinz B, Phan S H, Thannickal V J et al.. The myofibroblast: one function, multiple origins.  Am J Pathol. 2007;  170 1807-1816
  • 85 Hinz B. Formation and function of the myofibroblast during tissue repair.  J Invest Dermatol. 2007;  127 526-537
  • 86 Levens E, Luo X, Ding L et al.. 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. 2005;  11 489-494
  • 87 Luo X, Levens E, Williams R S et al.. The expression of Abl interactor 2 in leiomyoma and myometrium and regulation by GnRH analogue and transforming growth factor-beta.  Hum Reprod. 2006;  21 1380-1386
  • 88 ten Dijke P, Arthur H M. Extracellular control of TGFbeta signalling in vascular development and disease.  Nat Rev Mol Cell Biol. 2007;  8 857-869
  • 89 Ding L, Xu J, Luo X et al.. Gonadotropin releasing hormone and transforming growth factor beta activate mitogen-activated protein kinase/extracellularly regulated kinase and differentially regulate fibronectin, type I collagen, and plasminogen activator inhibitor-1 expression in leiomyoma and myometrial smooth muscle cells.  J Clin Endocrinol Metab. 2004;  89 5549-5557
  • 90 Kato M, Zhang J, Wang M et al.. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors.  Proc Natl Acad Sci U S A. 2007;  104 3432-3437
  • 91 Anderson C, Catoe H, Werner R. MIR-206 regulates connexin43 expression during skeletal muscle development.  Nucleic Acids Res. 2006;  34 5863-5871
  • 92 McCarthy J J, Esser K A. MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy.  J Appl Physiol. 2007;  102 306-313
  • 93 Dews M, Homayouni A, Yu D et al.. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster.  Nat Genet. 2006;  38 1060-1065
  • 94 Luo X, Ding L, Chegini N. 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. 2006;  12 245-256
  • 95 Leask A, Abraham D J. All in the CCN family: essential matricellular signaling modulators emerge from the bunker.  J Cell Sci. 2006;  119 4803-4810
  • 96 Sampath D, Zhu Y, Winneker R C et al.. Aberrant expression of Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, and dysregulation by 17 beta-estradiol and basic fibroblast growth factor in human uterine leiomyomas.  J Clin Endocrinol Metab. 2001;  86 1707-1715
  • 97 Bein K, Odell-Fiddler E T, Drinane M. Role of TGF-beta1 and JNK signaling in capillary tube patterning.  Am J Physiol Cell Physiol. 2004;  287 C1012-C1022
  • 98 Coller H A, Forman J J, Legesse-Miller A. “Myc'ed messages”: myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron.  PLoS Genet. 2007;  3 e146
  • 99 Hyder S M, Huang J C, Nawaz Z et al.. Regulation of vascular endothelial growth factor expression by estrogens and progestins.  Environ Health Perspect. 2000;  108(Suppl 5) 785-790
  • 100 Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis.  Trends Pharmacol Sci. 2008;  29 12-15
  • 101 Kuehbacher A, Urbich C, Zeiher A M et al.. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis.  Circ Res. 2007;  101 59-68
  • 102 Poliseno L, Tuccoli A, Mariani L et al.. MicroRNAs modulate the angiogenic properties of HUVECs.  Blood. 2006;  108 3068-3071
  • 103 Hua Z, Lv Q, Ye W et al.. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia.  PLoS One. 2006;  1 e116
  • 104 Lee D Y, Deng Z, Wang C H et al.. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression.  Proc Natl Acad Sci U S A. 2007;  104 20350-20355
  • 105 Weston G, Trajstman A C, Gargett C E et al.. Fibroids display an anti-angiogenic gene expression profile when compared with adjacent myometrium.  Mol Hum Reprod. 2003;  9 541-549
  • 106 Chen C Z, Lodish H F. MicroRNAs as regulators of mammalian hematopoiesis.  Semin Immunol. 2005;  17 155-165
  • 107 Li S C, Tang P, Lin W C. Intronic microRNA: discovery and biological implications.  DNA Cell Biol. 2007;  26 195-207
  • 108 Lodish H F, Zhou B, Liu G et al.. Micromanagement of the immune system by microRNAs.  Nat Rev Immunol. 2008;  8 120-130
  • 109 O'Connell R M, Taganov K D, Boldin M P et al.. MicroRNA-155 is induced during the macrophage inflammatory response.  Proc Natl Acad Sci U S A. 2007;  104 1604-1609
  • 110 Rodriguez A, Vigorito E, Clare S et al.. Requirement of bic/microRNA-155 for normal immune function.  Science. 2007;  316 608-611
  • 111 Costinean S, Zanesi N, Pekarsky Y et al.. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice.  Proc Natl Acad Sci U S A. 2006;  103 7024-7029
  • 112 Meng F, Henson R, Wehbe-Janek H et al.. The microRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes.  J Biol Chem. 2007;  282 8256-8264
  • 113 Meng F, Wehbe-Janek H, Henson R et al.. Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes.  Oncogene. 2008;  27 378-386
  • 114 Tili E, Michaille J J, Cimino A et al.. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.  J Immunol. 2007;  179 5082-5089
  • 115 Fontana L, Pelosi E, Greco P et al.. MicroRNAs 17–5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation.  Nat Cell Biol. 2007;  9 775-787
  • 116 Li Q J, Chau J, Ebert P J et al.. miR-181a is an intrinsic modulator of T cell sensitivity and selection.  Cell. 2007;  129 147-161
  • 117 Neilson J R, Zheng G X, Burge C B et al.. Dynamic regulation of miRNA expression in ordered stages of cellular development.  Genes Dev. 2007;  21 578-589

Xiaoping LuoM.D. 

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology

University of Florida, Gainesville, FL 32610

Email: Xiaoping@obgyn.ufl.edu

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