Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas.
BACKGROUND
Human uterine leiomyomas (ULM) are characterized by dysregulation of a large number of genes and non-coding regulatory microRNAs. In order to identify microRNA::mRNA associations relevant to ULM pathogenesis, we examined global correlation patterns between the altered microRNA expression and the predicted target genes in ULMs and matched myometria.


RESULTS
Patterns of inverse association of microRNA with mRNA expression in ULMs revealed an involvement of multiple candidate pathways, including extensive transcriptional reprogramming, cell proliferation control, MAP kinase, TGF-beta, WNT, JAK/STAT signaling, remodeling of cell adhesion, and cell-cell and cell-matrix contacts. We further examined the correlation between the expression of the selected target gene protein products and microRNAs in thirty-six paired sets of leiomyomas and matched myometria. We found that a number of dysregulated microRNAs were inversely correlated with their targets at the protein level. The comparative genomic hybridization (CGH) in eight ULM patients revealed that partially shared deletions of two distinct chromosomal regions might be responsible for loss of cancer-associated microRNA expression and could thus contribute to the ULM pathogenesis via deregulation of target mRNAs. Last, we functionally tested the repressor effects of selected cancer-related microRNAs on their predicted target genes in vitro.


CONCLUSIONS
We found that some but not all of the predicted and inversely correlated target genes in ULMs can be directly regulated by microRNAs in vitro. Our findings provide a broad overview of molecular events underlying the tumorigenesis of uterine ULMs and identify select genetic and regulatory events that alter microRNA expression and may play important roles in ULM pathobiology by positively regulating tumor growth while maintaining the non-invasive character of ULMs.
Zavadil
Jiri
J
Department of Pathology, School of Medicine, New York University, New York, New York, United States of America.
Ye
Huihui
H
Liu
Zhaojian
Z
Wu
JingJing
J
Lee
Peng
P
Hernando
Eva
E
Soteropoulos
Patricia
P
Toruner
Gokce A
GA
Wei
Jian-Jun
JJ
D000328:Adult; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D023281:Genomics; D006706:Homeostasis; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D035683:MicroRNAs; D011506:Proteins; D012333:RNA, Messenger
Nature. 2005 Feb 17;433(7027):769-73
15685193
Fertil Steril. 2008 Jun;89(6):1771-6
17765232
Nat Genet. 2005 Jul;37(7):766-70
15965474
Cell. 2005 Jan 14;120(1):15-20
15652477
PLoS One. 2010 Jan 13;5(1):e8697
20084174
PLoS One. 2007 Aug 29;2(8):e804
17726534
Nat Genet. 2005 May;37(5):495-500
15806104
Mol Cancer Res. 2008 Apr;6(4):663-73
18403645
Mol Cells. 2005 Feb 28;19(1):1-15
15750334
Genes Chromosomes Cancer. 2007 Apr;46(4):336-47
17243163
Cancer Res. 2005 Aug 15;65(16):7065-70
16103053
Dev Biol. 2007 Feb 1;302(1):1-12
16989803
Hum Reprod. 2006 Jan;21(1):57-67
16172143
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60
15284443
Ann Neurol. 1996 Dec;40(6):941-4
9007104
Science. 2007 Mar 16;315(5818):1576-9
17322030
Curr Opin Genet Dev. 2005 Oct;15(5):563-8
16099643
J Cell Mol Med. 2008 Jan-Feb;12(1):227-40
18182067
Genome Biol. 2003;4(5):P3
12734009
Biotechniques. 2003 Feb;34(2):374-8
12613259
Cell. 2005 Jul 15;122(1):6-7
16009126
Genes Chromosomes Cancer. 2004 Jul;40(3):204-17
15139000
Oncogene. 2007 May 14;26(22):3279-90
17496922
Endocrinology. 2005 Mar;146(3):1097-118
15604209
Fertil Steril. 2005 Aug;84(2):474-84
16084893
Mod Pathol. 2005 Feb;18(2):179-88
15467714
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
16477010
Mol Hum Reprod. 2003 Sep;9(9):541-9
12900513
Fertil Steril. 2004 Sep;82(3):639-49
15374708
Cells Tissues Organs. 2007;185(1-3):157-61
17587821
Nature. 2005 Jun 9;435(7043):834-8
15944708
Environ Health Perspect. 2003 Jun;111(8):1037-54
12826476
Genes Dev. 2007 May 1;21(9):1025-30
17437991
Cell. 2003 Dec 26;115(7):787-98
14697198
Cell Death Differ. 2010 Feb;17(2):215-20
19498445
J Oncol. 2010;2010:821717
20049172
Hum Reprod. 2005 Apr;20(4):852-63
15705628
J Soc Gynecol Investig. 2003 Apr;10(3):161-71
12699880
Lab Invest. 2002 Jun;82(6):719-28
12065682
Nucleic Acids Res. 2007;35(1):152-64
17158157
Acta Neuropathol. 1997 Dec;94(6):525-31
9444353
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D140-4
16381832
Gynecol Oncol. 2010 Jan;116(1):117-25
19854497
Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11400-5
17600087
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9740-4
15210942