title: miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis.
abstract: We have previously reported that leiomyoma expressed lower levels of miR-200c and elevated IL8 as compared to paired myometrium. Here we addressed the regulatory functions of miR-200c on the expression of inflammatory mediators and cellular viability using leiomyomas and paired myometrium and their isolated primary smooth muscle cells. Our results indicated that gain-of function or knockdown of miR-200c in leiomyoma smooth muscle cells (LSMC) regulated IL8 mRNA and protein expression through direct targeting of IKBKB and alteration of NF-kB activity. Additionally, leiomyoma expressed higher levels of phosphorylated IKBKB with no significant difference in the level of IKBKB mRNA and protein as compared to matched myometrium. Gain-of function of miR-200c in LSMC resulted in decreased IkBα phosphorylation and p65 nuclear translocation, which led to decreased p65 transcriptional activity of IL8 promoter, and increased caspase 3/7 activity which was not reversible following IL8 restoration. Collectively, our results suggest that NF-κB signaling pathway is a target of miR-200c regulatory function, and low level of miR-200c expression in leiomyoma by transcriptional regulation of inflammatory mediators such as IL8, in part account for development of leiomyomas.
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Tsai-Der
authors.initials: TD
authors.lastname: Chuang
authors.affiliation: Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Omid
authors.initials: O
authors.lastname: Khorram
mesh_terms: D000328:Adult; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D007889:Leiomyoma / Q000201:enzymology / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D053148:Caspase 3; D053179:Caspase 7
references.citation: Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
references.pmid: 20066113
references.citation: Fertil Steril. 2009 May;91(5 Suppl):2177-84
references.pmid: 18555241
references.citation: Oncogene. 2008 Sep 18;27(42):5643-7
references.pmid: 18504431
references.citation: J Biol Chem. 2005 Jun 3;280(22):21091-8
references.pmid: 15811852
references.citation: Aging (Albany NY). 2009 Apr;1(4):402-11
references.pmid: 20148189
references.citation: J Clin Endocrinol Metab. 2002 Aug;87(8):3921-7
references.pmid: 12161534
references.citation: J Biol Chem. 2004 Dec 17;279(51):53241-7
references.pmid: 15485852
references.citation: Nat Rev Genet. 2011 Feb;12(2):99-110
references.pmid: 21245828
references.citation: Oncogene. 2008 Aug 7;27(34):4712-23
references.pmid: 18408758
references.citation: J Biol Chem. 2011 Apr 1;286(13):11604-15
references.pmid: 21282106
references.citation: Biochem Biophys Res Commun. 2010 Nov 5;402(1):135-40
references.pmid: 20933503
references.citation: Reprod Sci. 2012 Aug;19(8):786-96
references.pmid: 22569286
references.citation: J Cell Sci. 2011 Dec 15;124(Pt 24):4161-71
references.pmid: 22223884
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):628-38
references.pmid: 18628784
references.citation: Endocr Relat Cancer. 2012 Jul 22;19(4):541-56
references.pmid: 22685266
references.citation: Cell. 2004 Apr 16;117(2):225-37
references.pmid: 15084260
references.citation: Bull Exp Biol Med. 2008 Jan;145(1):84-9
references.pmid: 19024011
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8231-6
references.pmid: 20406904
references.citation: Oncogene. 2008 Oct 6;27(45):5959-74
references.pmid: 18836476
references.citation: Mol Cell. 2010 Jun 25;38(6):908-15
references.pmid: 20620960
references.citation: Int J Mol Med. 2008 Sep;22(3):271-5
references.pmid: 18698484
references.citation: Mol Endocrinol. 2012 Jun;26(6):1028-42
references.pmid: 22556343
references.citation: Mol Hum Reprod. 2002 Dec;8(12):1071-8
references.pmid: 12468639
references.citation: J Pathol. 2008 Jan;214(2):199-210
references.pmid: 18161745
references.citation: Hepatology. 2007 Aug;46(2):590-7
references.pmid: 17661407
references.citation: J Immunol. 2003 Mar 15;170(6):3369-76
references.pmid: 12626597
references.citation: Breast Cancer Res. 2011 Apr 18;13(2):R45
references.pmid: 21501518
references.citation: Mol Cancer Ther. 2008 Sep;7(9):2649-61
references.pmid: 18790747
references.citation: J Mol Cell Biol. 2011 Jun;3(3):159-66
references.pmid: 21502305
references.citation: Cell Mol Immunol. 2009 Oct;6(5):327-34
references.pmid: 19887045
references.citation: Science. 1999 Apr 9;284(5412):309-13
references.pmid: 10195894
references.citation: Annu Rev Biochem. 2010;79:351-79
references.pmid: 20533884
references.citation: Oncogene. 2007 Nov 22;26(53):7445-56
references.pmid: 17563753
references.citation: Mediators Inflamm. 2012;2012:504952
references.pmid: 22685373
references.citation: Kidney Int. 2007 May;71(9):867-74
references.pmid: 17332736
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6735-41
references.pmid: 18980965
references.citation: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):721-9
references.pmid: 22247255
references.citation: J Cell Sci. 2010 Dec 15;123(Pt 24):4231-9
references.pmid: 21081648
references.citation: Ann Oncol. 2002 Mar;13(3):430-4
references.pmid: 11996475
references.citation: Am J Obstet Gynecol. 2001 Mar;184(4):559-66
references.pmid: 11262453
references.citation: Mol Hum Reprod. 2012 Mar;18(3):136-45
references.pmid: 21989168
references.citation: Oncogene. 2010 Jul 29;29(30):4297-306
references.pmid: 20514023
references.citation: J Cell Sci. 2008 Jul 1;121(Pt 13):2224-34
references.pmid: 18565826
references.citation: Nat Commun. 2013;4:2427
references.pmid: 24018975
references.citation: EMBO J. 1995 Jun 15;14(12):2876-83
references.pmid: 7796813
references.citation: Semin Reprod Med. 2010 May;28(3):180-203
references.pmid: 20414842
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13450-5
references.pmid: 20624982