title: Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions.
abstract: MicroRNAs (miRNAs) are small, noncoding RNAs involved in posttranscriptional regulation of protein-coding genes in various biological processes. In our preliminary miRNA microarray analysis, miR-375 was identified as the most underexpressed in human oral tumor versus controls. The purpose of the present study is to examine the function of miR-375 as a candidate tumor suppressor miRNA in oral cancer. Cancerous inhibitor of PP2A (CIP2A), a guardian of oncoprotein MYC, is identified as a candidate miR-375 target based on bioinformatics. Luciferase assay accompanied by target sequence mutagenesis elucidates five functional miR-375-binding sites clustered in the CIP2A coding sequence close to the C-terminal domain. Overexpression of CIP2A is clearly demonstrated in oral cancers, and inverse correlation between miR-375 and CIP2A is observed in the tumors, as well as in NCI-60 cell lines, indicating the potential generalized involvement of the miR-375-CIP2A relationship in many other cancers. Transient transfection of miR-375 in oral cancer cells reduces the expression of CIP2A, resulting in decrease of MYC protein levels and leading to reduced proliferation, colony formation, migration, and invasion. Therefore this study shows that underexpression of tumor suppressor miR-375 could lead to uncontrolled CIP2A expression and extended stability of MYC, which contributes to promoting cancerous phenotypes.
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Jung
authors.forename: Rushi S
authors.initials: RS
authors.lastname: Patel
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Phillips
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.forename: Donald M
authors.initials: DM
authors.lastname: Cohen
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
authors.forename: Edward K L
authors.initials: EK
authors.lastname: Chan
mesh_terms: D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016366:Open Reading Frames; D061251:Primary Cell Culture; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014059:Tongue / Q000378:metabolism / Q000473:pathology
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; C540933:MIRN375 microRNA, human; C489427:MYC protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D008156:Luciferases
references.citation: Genome Res. 2009 Jan;19(1):92-105
references.pmid: 18955434
references.citation: Oncogene. 2002 Jul 25;21(32):5006-15
references.pmid: 12118381
references.citation: Nature. 2008 Oct 23;455(7216):1124-8
references.pmid: 18806776
references.citation: Genetica. 2009 Nov;137(2):159-64
references.pmid: 19578934
references.citation: Nature. 2008 Sep 4;455(7209):58-63
references.pmid: 18668040
references.citation: Biochim Biophys Acta. 2007 Jun;1775(2):274-82
references.pmid: 17189674
references.citation: Nat Genet. 2005 May;37(5):495-500
references.pmid: 15806104
references.citation: J Clin Oncol. 2005 Jan 10;23(2):346-56
references.pmid: 15637397
references.citation: Clin Cancer Res. 2011 Dec 15;17(24):7539-50
references.pmid: 22031094
references.citation: Nucleic Acids Res. 2007;35(7):2333-42
references.pmid: 17389647
references.citation: Nat Rev Drug Discov. 2010 Oct;9(10):775-89
references.pmid: 20885409
references.citation: Head Neck. 2002 Feb;24(2):165-80
references.pmid: 11891947
references.citation: Annu Rev Biomed Eng. 2010 Aug 15;12:1-27
references.pmid: 20415587
references.citation: Am J Pathol. 2012 Mar;180(3):917-928
references.pmid: 22234174
references.citation: Br J Cancer. 2011 Dec 6;105(12):1905-11
references.pmid: 22075943
references.citation: J Hum Genet. 2011 Aug;56(8):595-601
references.pmid: 21753766
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3903-8
references.pmid: 18308936
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12085-90
references.pmid: 19597153
references.citation: Clin Cancer Res. 2009 Aug 15;15(16):5092-100
references.pmid: 19671842
references.citation: Cell Cycle. 2008 Mar 1;7(5):592-6
references.pmid: 18256542
references.citation: Cell. 2005 Mar 11;120(5):635-47
references.pmid: 15766527
references.citation: J Biol Chem. 2012 Aug 24;287(35):29261-72
references.pmid: 22761427
references.citation: Cancer Biol Ther. 2010 Oct 1;10(7):694-9
references.pmid: 21068540
references.citation: PLoS One. 2011 Mar 22;6(3):e18067
references.pmid: 21445367
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references.pmid: 16461460
references.citation: Nat Rev Cancer. 2006 Apr;6(4):259-69
references.pmid: 16557279
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6
references.pmid: 18755897
references.citation: Oncogene. 2007 Apr 26;26(19):2799-803
references.pmid: 17072344
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14879-84
references.pmid: 18812516
references.citation: Nucleic Acids Res. 2004 Dec 07;32(21):6284-91
references.pmid: 15585662
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15472-7
references.pmid: 17875987
references.citation: Nat Protoc. 2007;2(2):329-33
references.pmid: 17406593
references.citation: Mol Cell Biol. 2010 Sep;30(17):4197-210
references.pmid: 20584986
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2850-5
references.pmid: 19351747
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3722-8
references.pmid: 18559589
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9667-72
references.pmid: 17535905
references.citation: Nucleic Acids Res. 2011 Oct;39(18):8163-72
references.pmid: 21724616
references.citation: Community Dent Oral Epidemiol. 2000 Aug;28(4):249-56
references.pmid: 10901403
references.citation: Curr Mol Med. 2008 Sep;8(6):446-58
references.pmid: 18781952
references.citation: J Immunol. 2010 Jun 15;184(12):6773-81
references.pmid: 20483747
references.citation: Cell Res. 2010 Jul;20(7):784-93
references.pmid: 20548334
references.citation: Ann Surg Oncol. 2011 Mar;18(3):857-65
references.pmid: 20842459
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Cell. 2012 Mar 30;149(1):22-35
references.pmid: 22464321
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Cancer Res. 2010 Mar 15;70(6):2339-49
references.pmid: 20215506
references.citation: Cell. 2007 Jul 13;130(1):51-62
references.pmid: 17632056
references.citation: Cell. 2005 Jan 14;120(1):15-20
references.pmid: 15652477
references.citation: Hepatology. 2008 Jun;47(6):1955-63
references.pmid: 18433021
references.citation: Nat Methods. 2007 Apr;4(4):359-65
references.pmid: 17396127
references.citation: Bioinformatics. 2012 Mar 15;28(6):771-6
references.pmid: 22285563
references.citation: Nature. 2004 Sep 16;431(7006):350-5
references.pmid: 15372042
references.citation: Cell. 2002 Aug 23;110(4):513-20
references.pmid: 12202040
references.citation: Science. 2002 Sep 20;297(5589):2053-6
references.pmid: 12242443
references.citation: Cancer Res. 2012 Jul 15;72(14):3499-511
references.pmid: 22802077
references.citation: RNA. 2008 May;14(5):872-7
references.pmid: 18367714
references.citation: Gut. 2012 Jan;61(1):33-42
references.pmid: 21813472
references.citation: J Calif Dent Assoc. 2009 Nov;37(11):789-98
references.pmid: 19998655
references.citation: Med Oral Patol Oral Cir Bucal. 2011 May 01;16(3):e300-5
references.pmid: 21441877
references.citation: Nature. 2008 Sep 4;455(7209):64-71
references.pmid: 18668037
references.citation: Genes Dev. 2004 Jan 15;18(2):132-7
references.pmid: 14729570
references.citation: Am J Pathol. 2011 Nov;179(5):2580-8
references.pmid: 21945323
references.citation: PLoS One. 2011 Jan 31;6(1):e16250
references.pmid: 21305018
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D202-9
references.pmid: 21037263
references.citation: Prostate. 2005 May 15;63(3):252-8
references.pmid: 15538718
references.citation: Genome Biol. 2003;5(1):R1
references.pmid: 14709173
references.citation: Cell. 2006 Sep 22;126(6):1203-17
references.pmid: 16990141
references.citation: Genes Dev. 2003 May 1;17(9):1115-29
references.pmid: 12695333