STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer.
A transient inflammatory signal can initiate an epigenetic switch from nontransformed to cancer cells via a positive feedback loop involving NF-kappaB, Lin28, let-7, and IL-6. We identify differentially regulated microRNAs important for this switch and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL-6, directly activates miR-21 and miR-181b-1. Remarkably, transient expression of either microRNA induces the epigenetic switch. MiR-21 and miR-181b-1, respectively, inhibit PTEN and CYLD tumor suppressors, leading to increased NF-kappaB activity required to maintain the transformed state. These STAT3-mediated regulatory circuits are required for the transformed state in diverse cell lines and tumor growth in xenografts, and their transcriptional signatures are observed in colon adenocarcinomas. Thus, STAT3 is not only a downstream target of IL-6 but, with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer.
Iliopoulos
Dimitrios
D
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Jaeger
Savina A
SA
Hirsch
Heather A
HA
Bulyk
Martha L
ML
Struhl
Kevin
K
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019295:Computational Biology; D000074749:Deubiquitinating Enzyme CYLD; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007700:Kinetics; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018836:Inflammation Mediators; C524940:MIRN21 microRNA, human; C540193:MIrn181 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
Science. 2008 Apr 4;320(5872):97-100
18292307
Nat Methods. 2008 Apr;5(4):347-53
18311145
Science. 2007 Mar 16;315(5818):1576-9
17322030
Nat Rev Immunol. 2007 Jan;7(1):41-51
17186030
Cancer Cell. 2009 Feb 3;15(2):103-13
19185845
Brain Res. 2008 Oct 21;1236:185-93
18710654
J Biol Chem. 2008 Jan 11;283(2):1026-33
17991735
JAMA. 2008 Jan 30;299(4):425-36
18230780
Nature. 2003 Aug 14;424(6950):797-801
12917690
Cell. 2008 Aug 8;134(3):521-33
18692474
Nat Struct Mol Biol. 2009 Oct;16(10):1021-5
19713958
Nat Biotechnol. 2006 Nov;24(11):1429-35
16998473
Cancer Lett. 2007 Jun 28;251(2):199-210
17129668
Cancer Cell. 2010 Apr 13;17(4):348-61
20385360
EMBO J. 2009 Oct 21;28(20):3157-70
19745813
Genes Dev. 2008 Nov 15;22(22):3172-83
19056895
Cell. 2009 Nov 13;139(4):693-706
19878981
Blood. 2007 Aug 15;110(4):1330-3
17496199
Hum Mol Genet. 2009 Dec 15;18(24):4818-29
19776030
Cell. 2005 Mar 11;120(5):635-47
15766527
Oncogene. 2008 Sep 18;27(41):5497-510
18794884
Cell Cycle. 2009 Sep 1;8(17):2756-68
19652553
Nat Rev Cancer. 2009 Nov;9(11):798-809
19851315
Cell. 1999 Aug 6;98(3):295-303
10458605
RNA. 2008 Nov;14(11):2348-60
18812439
Cell. 2008 Jun 27;133(7):1266-76
18585359
Nature. 2003 Aug 14;424(6950):793-6
12917689
J Neurooncol. 2009 Jul;93(3):325-32
19159078
Gastroenterology. 2007 Aug;133(2):647-58
17681183
Nature. 2005 Jun 9;435(7043):839-43
15944709
Science. 2009 Jun 26;324(5935):1720-3
19443739
Oncogene. 2009 Jan 29;28(4):509-17
18997818
Cell. 2009 Jan 23;136(2):215-33
19167326
Nature. 2008 Jan 10;451(7175):147-52
18185580
Leuk Res. 2009 Feb;33(2):288-96
18640717
Nat Genet. 2008 Jan;40(1):43-50
18066065