A micro‐RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas

Human uterine leiomyomas (ULMs) are the most common neoplasms of women. Many genes are dysregulated in ULMs and some of this dysregulation may be due to abnormal expression of micro‐RNAs (miRNAs). In this study, 55 ULMs and matched myometrium were collected from 41 patients for microarray‐based global miRNA expression analysis. Of 206 miRNAs examined, 45 miRNAs were significantly up‐ or down‐regulated in ULMs in comparison to the matched myometrium (P < 0.001). The top five dysregulated miRNAs in ULMs are the let‐7 family, miR‐21, miR‐23b, miR‐29b, and miR‐197. Four polycistronic clusters of miRNAs were either up‐ or down‐regulated, but not in a mixed pattern, indicative of coordinated regulation of these miRNAs. Significance analysis revealed that subsets of miRNAs were strongly associated with tumor sizes and race. By prediction analysis we identified some important tumorigenic genes previously identified in ULMs that may be targeted by the dysregulated miRNAs. HMGA2 was identified as one of target genes of the let‐7 family of miRNAs and has been found to be suppressed by let‐7 in vitro. (This article contains Supplementary material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat.) © 2007 Wiley‐Liss, Inc.

[1]  Wen-Hsiung Li,et al.  Fundamentals of molecular evolution , 1990 .

[2]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[3]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[4]  L. Aaltonen,et al.  7q deletion mapping and expression profiling in uterine fibroids , 2005, Oncogene.

[5]  U. Fuhrmann,et al.  Misexpression of wild-type and truncated isoforms of the high-mobility group I proteins HMGI-C and HMGI(Y) in uterine leiomyomas. , 1999, The American journal of pathology.

[6]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[7]  L. Aaltonen,et al.  Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. , 2004, The American journal of pathology.

[8]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[9]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[10]  J. Manson,et al.  Variation in the Incidence of Uterine Leiomyoma Among Premenopausal Women by Age and Race , 1997, Obstetrics and gynecology.

[11]  Jeffrey Shelton,et al.  An optimized isolation and labeling platform for accurate microRNA expression profiling. , 2005, RNA.

[12]  L. Orozco,et al.  Alport syndrome and diffuse leiomyomatosis. Clinical aspects, pathology, molecular biology and extracellular matrix studies. A synthesis. , 2000, Nephrologie.

[13]  H. Peterson,et al.  Hysterectomy in the United States, 1988‐1990 , 1994, Obstetrics and gynecology.

[14]  N. Iwai,et al.  Assessment of the MicroRNA System in Salt-Sensitive Hypertension , 2005, Hypertension Research.

[15]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[16]  M. Perola,et al.  Heritability and risk factors of uterine fibroids--the Finnish Twin Cohort study. , 2000, Maturitas.

[17]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A I Saeed,et al.  TM4: a free, open-source system for microarray data management and analysis. , 2003, BioTechniques.

[19]  J. Bullerdiek,et al.  Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells. , 1999, Molecular human reproduction.

[20]  S. Weremowicz,et al.  HMGA2 expression in uterine leiomyomata and myometrium: Quantitative analysis and tissue culture studies , 2003, Genes, chromosomes & cancer.

[21]  A. Al-Hendy,et al.  Ethnic distribution of estrogen receptor-alpha polymorphism is associated with a higher prevalence of uterine leiomyomas in black Americans. , 2006, Fertility and sterility.

[22]  A. Al-Hendy,et al.  Catechol-O-Methyltransferase Polymorphism Is Associated With Increased Uterine Leiomyoma Risk in Different Ethnic Groups , 2006, The Journal of the Society for Gynecologic Investigation: JSGI.

[23]  J. Melamed,et al.  Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata. , 2006, Human reproduction.

[24]  M. Tang,et al.  Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review. , 2005, Human reproduction.

[25]  C. Steiner,et al.  Hysterectomy Rates in the United States 1990–1997 , 2002, Obstetrics and gynecology.

[26]  C. Croce,et al.  The role of microRNA genes in papillary thyroid carcinoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Y. Trotsenko,et al.  Fundamentals of molecular evolution, 2nd Edition. By Dan Graur and Wen-Hsiung Li, Sinauer Associates, Inc, Sanderland, Massachusetts, 2000, xiv + 481 pp, price £27.95. ISBN 0 87893 266 6 , 2001 .

[28]  L. Chiriboga,et al.  Spatial differences in biologic activity of large uterine leiomyomata. , 2006, Fertility and sterility.

[29]  Hanah Margalit,et al.  Clustering and conservation patterns of human microRNAs , 2005, Nucleic acids research.

[30]  P. Rogalla,et al.  HMGIC expressed in a uterine leiomyoma with a deletion of the long arm of chromosome 7 along with a 12q14-15 rearrangement but not in tumors showing del(7) as the sole cytogenetic abnormality. , 1997, Cancer genetics and cytogenetics.

[31]  Dan Graur,et al.  Fundamentals of Molecular Evolution, 2nd Edition , 2000 .

[32]  P. Cin,et al.  Uterine Leiomyomata with t(10;17) Disrupt the Histone Acetyltransferase MORF , 2004, Cancer Research.

[33]  K. Hirschhorn,et al.  Molecular cytogenetic analysis of uterine leiomyoma and leiomyosarcoma by comparative genomic hybridization. , 2000, Cancer genetics and cytogenetics.

[34]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[35]  David B Dunson,et al.  High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. , 2003, American journal of obstetrics and gynecology.

[36]  D. Spiegelman,et al.  Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: a prospective study. , 2004, American journal of epidemiology.

[37]  C. Morton,et al.  Leiomyomata: heritability and cytogenetic studies. , 2001, Human reproduction update.

[38]  P. Stolley,et al.  Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. , 1996, The Journal of reproductive medicine.

[39]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Common,et al.  Pregnancy After Uterine Artery Embolization for Leiomyomata:: The Ontario Multicenter Trial , 2005, Obstetrics and gynecology.

[41]  R. Cantor,et al.  Cytogenetic abnormalities in uterine myomas are associated with myoma size. , 1998, Molecular human reproduction.

[42]  Yuriy Gusev,et al.  Real-time expression profiling of microRNA precursors in human cancer cell lines , 2005, Nucleic acids research.

[43]  D. Dixon,et al.  Etiology and pathogenesis of uterine leiomyomas: a review. , 2003, Environmental health perspectives.

[44]  E. Miska,et al.  MicroRNA functions in animal development and human disease , 2005, Development.

[45]  B. Reinhart,et al.  Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA , 2000, Nature.

[46]  M. Amarzguioui,et al.  Approaches for chemically synthesized siRNA and vector‐mediated RNAi , 2005, FEBS letters.

[47]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[48]  Isaac Bentwich.  Available online , 2005 .

[49]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[50]  R. Kudo,et al.  Familial aggregation of uterine myomas in Japanese women. , 2002, Journal of epidemiology.

[51]  D. Wotton,et al.  TGIF Inhibits Retinoid Signaling , 2006, Molecular and Cellular Biology.