title: Enhanced IL-6/IL-6R signaling promotes growth and malignant properties in EBV-infected premalignant and cancerous nasopharyngeal epithelial cells.
abstract: Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells.
authors: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors: Guitao
authors: G
authors: Zhang
authors: Chi Man
authors: CM
authors: Tsang
authors: Wen
authors: W
authors: Deng
authors: Yim Ling
authors: YL
authors: Yip
authors: Vivian Wai-Yan
authors: VW
authors: Lui
authors: Sze Chuen Cesar
authors: SC
authors: Wong
authors: Annie Lai-Man
authors: AL
authors: Cheung
authors: Pok Man
authors: PM
authors: Hau
authors: Musheng
authors: M
authors: Zeng
authors: Maria Li
authors: ML
authors: Lung
authors: Honglin
authors: H
authors: Chen
authors: Kwok Wai
authors: KW
authors: Lo
authors: Kenzo
authors: K
authors: Takada
authors: Sai Wah
authors: SW
authors: Tsao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009368:Neoplasm Transplantation; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014763:Viral Matrix Proteins
references: Semin Cancer Biol. 1992 Oct;3(5):297-307
references: 1335793
references: Carcinogenesis. 2009 Dec;30(12):2085-94
references: 19843642
references: Oncogene. 2000 May 15;19(21):2548-56
references: 10851053
references: Neoplasia. 2006 Mar;8(3):173-80
references: 16611410
references: Int J Cancer. 2009 Oct 15;125(8):1884-93
references: 19588483
references: Cancer Res. 1987 Jun 15;47(12):3239-45
references: 2438036
references: J Virol. 2003 Apr;77(7):4139-48
references: 12634372
references: J Biol Chem. 2003 Oct 3;278(40):38829-39
references: 12832423
references: J Surg Oncol. 1986 Apr;31(4):229-34
references: 3724177
references: Eur J Cancer. 2005 Nov;41(16):2502-12
references: 16199153
references: Nat Rev Cancer. 2004 Oct;4(10):757-68
references: 15510157
references: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10602-7
references: 15249664
references: Cancer Cell. 2004 May;5(5):423-8
references: 15144950
references: Clin Cancer Res. 2002 Apr;8(4):945-54
references: 11948098
references: J Pathol. 2012 Feb;226(3):471-81
references: 22009689
references: Lab Invest. 2003 May;83(5):697-709
references: 12746479
references: Cancer Cell. 2011 Apr 12;19(4):456-69
references: 21481788
references: Int J Mol Med. 2008 Feb;21(2):153-62
references: 18204781
references: Virchows Arch. 2006 Nov;449(5):513-9
references: 17033798
references: J Virol. 2001 Mar;75(6):2929-37
references: 11222718
references: Int J Cancer. 2010 Oct 1;127(7):1570-83
references: 20091869
references: Nat Rev Cancer. 2009 Nov;9(11):798-809
references: 19851315
references: Cell. 1999 Aug 6;98(3):295-303
references: 10458605
references: Semin Cancer Biol. 2012 Apr;22(2):127-36
references: 22249142
references: Oncogene. 1997 Jun 19;14(24):2899-916
references: 9205097
references: Int J Cancer. 2008 Jun 1;122(11):2517-25
references: 18307254
references: Cancer Res. 2009 Jan 15;69(2):632-9
references: 19147578
references: Oncogene. 2000 May 15;19(21):2468-73
references: 10851045
references: Nat Med. 2005 Jun;11(6):595-6
references: 15937466
references: Int J Cancer. 2006 Oct 1;119(7):1567-76
references: 16688717
references: J Virol. 1992 May;66(5):2689-97
references: 1313894
references: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):E3473-82
references: 23161911
references: Semin Cancer Biol. 2012 Apr;22(2):137-43
references: 22497025