title: Coordinated targeting of the EGFR signaling axis by microRNA-27a*.
abstract: Epidermal growth factor receptor (EGFR) has been characterized as a critical factor in the development and progression of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC). However, monotherapy with EGFR-specific agents has not been as dramatic as preclinical studies have suggested. Since complex regulation of the EGFR signaling axis might confound current attempts to inhibit EGFR directly, we searched for microRNAs (miRNAs) that may target the EGFR signaling axis. We identified miR-27a (miR-27a-3p) and its complementary or star (*) strand, miR-27a* (miR-27a-5p), as novel miRNAs targeting EGFR, which were significantly downregulated in multiple HNSCC cell lines. Analysis of human specimens demonstrated that miR-27a* is significantly underexpressed in HNSCC as compared to normal mucosa. Increased expression of miR-27a* in HNSCC produced a profound cytotoxic effect not seen with miR-27a. Analysis for potential targets of miR-27a* led to the identification of AKT1 (protein kinase B) and mTOR (mammalian target of rapamycin) within the EGFR signaling axis. Treatment with miR-27a* led to coordinated downregulation of EGFR, AKT1 and mTOR. Overexpression of EGFR signaling pathway components decreased the overall effect of miR-27a* on HNSCC cell viability. Constitutive and inducible expression of miR-27a* in a murine orthotopic xenograft model of oral cavity cancer led to decreased tumor growth. Direct intratumoral injection of miR-27a* inhibited tumor growth in vivo. These findings identify miR-27a* as a functional star sequence that exhibits novel coordinated regulation of the EGFR pathway in solid tumors and potentially represents a novel therapeutic option.
authors: Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Xiaoli
authors: X
authors: Wu
authors: Mihir K
authors: MK
authors: Bhayani
authors: Cristina T
authors: CT
authors: Dodge
authors: Milena S
authors: MS
authors: Nicoloso
authors: Yunyun
authors: Y
authors: Chen
authors: Xiaofeng
authors: X
authors: Yan
authors: Makoto
authors: M
authors: Adachi
authors: Ligy
authors: L
authors: Thomas
authors: Chad E
authors: CE
authors: Galer
authors: Tilahun
authors: T
authors: Jiffar
authors: Curtis R
authors: CR
authors: Pickering
authors: Michael E
authors: ME
authors: Kupferman
authors: Jeffrey N
authors: JN
authors: Myers
authors: George A
authors: GA
authors: Calin
authors: Stephen Y
authors: SY
authors: Lai
mesh_terms: D000818:Animals; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
references: PLoS One. 2010 Jun 30;5(6):e11387
references: 20613982
references: Nat Chem Biol. 2006 Dec;2(12):711-9
references: 17108989
references: Cancer Res. 2010 Nov 1;70(21):8822-31
references: 20978205
references: Nat Rev Cancer. 2006 Apr;6(4):259-69
references: 16557279
references: Ann Oncol. 2011 May;22(5):1078-1087
references: 21048039
references: Cancer Res. 1997 Jul 1;57(13):2681-6
references: 9205077
references: Ann Oncol. 2007 May;18(5):962
references: 17442660
references: J Clin Oncol. 2008 Jul 20;26(21):3582-9
references: 18559875
references: J Natl Cancer Inst. 1998 Jun 3;90(11):824-32
references: 9625170
references: J Biol Chem. 1999 Feb 12;274(7):4266-72
references: 9933627
references: Nat Rev Genet. 2011 Jan;12(1):19-31
references: 21116305
references: Mutat Res. 2012 Mar 1;731(1-2):14-9
references: 22085809
references: Nucleic Acids Res. 2004 Feb 09;32(3):893-901
references: 14769947
references: PLoS Med. 2005 Nov;2(11):e313
references: 16187797
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
references: 14973191
references: J Clin Oncol. 2007 Jun 1;25(16):2171-7
references: 17538161
references: Nat Med. 2008 Oct;14(10):1036-40
references: 18841144
references: Clin Cancer Res. 2010 Dec 15;16(24):5972-80
references: 21169250
references: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12085-90
references: 19597153
references: Cancer. 2007 Apr 15;109(8):1561-9
references: 17354229
references: Nat Struct Mol Biol. 2008 Apr;15(4):354-63
references: 18376413
references: World J Gastroenterol. 2009 Jan 28;15(4):431-40
references: 19152447
references: Cancer Res. 2002 Dec 15;62(24):7350-6
references: 12499279
references: Nature. 2005 Dec 1;438(7068):685-9
references: 16258535
references: RNA. 2010 Jan;16(1):43-56
references: 19917635
references: Nature. 2008 Oct 23;455(7216):1124-8
references: 18806776
references: J Clin Pathol. 2006 Jun;59(6):611-7
references: 16603649
references: Oncogene. 2011 Sep 8;30(36):3875-86
references: 21460851
references: J Clin Oncol. 2005 Nov 1;23(31):8081-92
references: 16204011
references: Nat Clin Pract Oncol. 2005 Jun;2(6):284-5
references: 16264980
references: BMC Cancer. 2011 Jan 25;11:31
references: 21266046
references: Cancer Lett. 2010 Dec 8;298(2):150-8
references: 20638779
references: J Intern Med. 2010 Jan;267(1):44-53
references: 20059643
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: Cancer Res. 2008 May 15;68(10):3566-72
references: 18483236
references: Nat Rev Genet. 2008 Feb;9(2):102-14
references: 18197166
references: Mol Ther. 2011 Jun;19(6):1116-22
references: 21427705
references: Oncogene. 2005 Jun 23;24(27):4442-9
references: 15856028
references: Cancer Res. 2005 Aug 1;65(15):6910-8
references: 16061675
references: Oncologist. 2010;15(9):994-1001
references: 20798198
references: Cell. 2005 Dec 29;123(7):1267-77
references: 16377567
references: Mol Cell. 2009 Apr 10;34(1):58-67
references: 19268617
references: Am J Clin Oncol. 2010 Jun;33(3):217-20
references: 19745694
references: Br J Cancer. 2009 Jan 13;100(1):89-95
references: 19088718
references: Cell. 2004 Jan 23;116(2):281-97
references: 14744438
references: Ann Oncol. 2008 Jun;19(6):1053-9
references: 18304967
references: JAMA. 2007 Jul 4;298(1):70-82
references: 17609492
references: RNA. 2011 Feb;17(2):312-26
references: 21177881
references: Cancer. 2008 Oct 1;113(7 Suppl):1911-32
references: 18798532
references: Clin Cancer Res. 2010 May 1;16(9):2489-95
references: 20406834
references: N Engl J Med. 2006 Feb 9;354(6):567-78
references: 16467544