title: Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer.
abstract: Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300) that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Hideo
authors.initials: H
authors.lastname: Hidaka
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C558811:MIRN574 microRNA, human; D035683:MicroRNAs; D019833:Genistein
references.citation: Br J Cancer. 2009 Dec 15;101(12):1949-56
references.pmid: 19888222
references.citation: Methods Mol Biol. 2011;676:147-63
references.pmid: 20931396
references.citation: Nat Rev Cancer. 2006 Jun;6(6):449-58
references.pmid: 16723991
references.citation: Nutr Rev. 2010 Sep;68(9):542-55
references.pmid: 20796219
references.citation: Cancer Res. 2001 Feb 15;61(4):1699-706
references.pmid: 11245486
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W317-22
references.pmid: 19465387
references.citation: Prostate. 2012 Aug 1;72(11):1171-8
references.pmid: 22161865
references.citation: Br J Cancer. 2010 Mar 2;102(5):883-91
references.pmid: 20160723
references.citation: J Nutr Biochem. 2012 Jul;23(7):691-8
references.pmid: 22704055
references.citation: Cancer Res. 2010 Apr 1;70(7):2809-18
references.pmid: 20332239
references.citation: Genome Res. 2009 Jan;19(1):92-105
references.pmid: 18955434
references.citation: Dev Biol. 2007 Feb 1;302(1):1-12
references.pmid: 16989803
references.citation: Clin Cancer Res. 2009 May 15;15(10):3251-5
references.pmid: 19447877
references.citation: J Nutr Biochem. 2007 Jun;18(6):408-17
references.pmid: 17142033
references.citation: PLoS One. 2012;7(8):e43812
references.pmid: 22928040
references.citation: Int J Cancer. 2006 Sep 15;119(6):1322-9
references.pmid: 16642477
references.citation: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W478-83
references.pmid: 22573175
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: Neoplasia. 2004 Jul-Aug;6(4):354-63
references.pmid: 15256057
references.citation: Exp Biol Med (Maywood). 2011 Jun 1;236(6):714-22
references.pmid: 21571909
references.citation: PLoS One. 2012;7(7):e40955
references.pmid: 22815877
references.citation: Int J Oncol. 2012 Apr;40(4):951-9
references.pmid: 22179486
references.citation: Clin Cancer Res. 2002 Nov;8(11):3438-44
references.pmid: 12429632
references.citation: Nat Genet. 2002 Apr;30(4):363-4
references.pmid: 11896390
references.citation: Cancer Prev Res (Phila). 2011 Jan;4(1):76-86
references.pmid: 21071579
references.citation: Genome Biol. 2007;8(1):R3
references.pmid: 17204154
references.citation: J Biol Chem. 2003 Apr 18;278(16):14013-9
references.pmid: 12588875
references.citation: J Nutr. 2002 Dec;132(12):3623-31
references.pmid: 12468598
references.citation: Cancer Res. 2010 Apr 15;70(8):3382-90
references.pmid: 20395211
references.citation: Cancer Metastasis Rev. 2010 Sep;29(3):465-82
references.pmid: 20730632
references.citation: J Hum Genet. 2012 Nov 26;57(11):691-9
references.pmid: 22854542
references.citation: Cancer Invest. 2010 Dec;28(10):1024-30
references.pmid: 20874002
references.citation: Angiogenesis. 2011 Dec;14(4):457-66
references.pmid: 21789714
references.citation: Biochem Biophys Res Commun. 2012 Apr 6;420(2):411-6
references.pmid: 22426479
references.citation: PLoS One. 2012;7(2):e31060
references.pmid: 22347428
references.citation: Cancer Res. 2008 May 15;68(10):3566-72
references.pmid: 18483236
references.citation: Int J Oncol. 2011 Jul;39(1):13-21
references.pmid: 21519788
references.citation: Nat Rev Mol Cell Biol. 2009 Feb;10(2):141-8
references.pmid: 19145236
references.citation: Cancer Lett. 2011 Aug 1;307(1):26-36
references.pmid: 21463919
references.citation: Mol Pharmacol. 2006 Sep;70(3):869-77
references.pmid: 16772519
references.citation: Oncol Rep. 2012 Jun;27(6):1967-75
references.pmid: 22407299
references.citation: Cancer Res. 2010 Feb 15;70(4):1486-95
references.pmid: 20124483
references.citation: Science. 1998 Aug 28;281(5381):1309-12
references.pmid: 9721092
references.citation: Nat Rev Genet. 2009 Oct;10(10):704-14
references.pmid: 19763153
references.citation: Nat Rev Cancer. 2010 Jun;10(6):389-402
references.pmid: 20495573
references.citation: RNA Biol. 2011 Jan-Feb;8(1):125-31
references.pmid: 21289483
references.citation: Biol Cell. 2000 Dec;92(8-9):595-604
references.pmid: 11374438
references.citation: Curr Top Med Chem. 2012;12(8):920-6
references.pmid: 22352917
references.citation: Cancer Res. 2005 Apr 15;65(8):3470-8
references.pmid: 15833883
references.citation: Prostate. 2006 Sep 15;66(13):1437-44
references.pmid: 16741920
references.citation: Hepatology. 2010 Sep;52(3):1164-6
references.pmid: 20812359
references.citation: Clin Cancer Res. 2002 Jul;8(7):2369-77
references.pmid: 12114442
references.citation: Cancer. 2008 Sep 1;113(5):1097-106
references.pmid: 18666210
references.citation: Int Immunopharmacol. 2012 Aug;13(4):468-75
references.pmid: 22683180
references.citation: Endocr Relat Cancer. 2010 Jan 29;17(1):R39-52
references.pmid: 19926708