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Role of the Epstein–Barr virus-encoded latent membrane protein-1, LMP1, in the pathogenesis of nasopharyngeal carcinoma

    Mhairi A Morris

    Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    ,
    Christopher W Dawson

    Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    &
    Lawrence S Young

    † Author for correspondence

    Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

    Published Online:https://doi.org/10.2217/fon.09.53

    Although frequently expressed in Epstein–Barr virus (EBV)-positive malignancies, the contribution of the oncogenic latent membrane protein-1 (LMP1) to the pathogenesis of nasopharyngeal carcinoma remains to be fully defined. As a key effector in EBV-driven B-cell transformation in vitro, LMP1 also displays oncogenic properties in rodent fibroblasts, and exhibits similar effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a plethora of signaling pathways including: NF-κB, JNK/p38 (SAPK), PI3-kinase and ERK–MPK. The constitutive activation of these pathways appears central in the ability of LMP1 to induce multiple morphological and phenotypic alterations. Here we review the effects of LMP1 on epithelial cell growth transformation, and its putative role in the pathogenesis of nasopharyngeal carcinoma, focusing on key areas of proliferation, survival, cell motility and invasion.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Young LS, Rickinson AB: Epstein–Barr virus: 40 years on. Nat. Rev. Cancer4(10),757–768 (2004).▪▪ Timely review of the research highlights in the field since the original discovery of the virus.
    • Chan AS, To KF, Lo KW et al.: High frequency of chromosome 3p deletion in histologically normal nasopharyngeal epithelia from southern Chinese. Cancer Res.60(19),5365–5370 (2000).
    • Chan AS, To KF, Lo KW et al.: Frequent chromosome 9p losses in histologically normal nasopharyngeal epithelia from southern Chinese. Int. J. Cancer102(3),300–303 (2002).
    • Pathmanathan R, Prasad U, Sadler R, Flynn K, Raab-Traub N: Clonal proliferations of cells infected with Epstein–Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N. Engl. J. Med.333(11),693–698 (1995).▪▪ Critical findings demonstrating that Epstein–Barr virus infection is an early event that occurs prior to clonal expansion of a premalignant pool of cells.
    • Wang D, Liebowitz D, Kieff E: An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell43(3 Part 2),831–840 (1985).
    • Baichwal VR, Sugden B: Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein–Barr virus. Oncogene2(5),461–467 (1988).
    • Kaye KM, Izumi KM, Kieff E: Epstein–Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc. Natl. Acad. Sci. USA90(19),9150–9154 (1993).▪ A key study in establishing the role of latent membrane protein 1 (LMP1) in the transformation of B cells.
    • Fahraeus R, Rymo L, Rhim JS, Klein G: Morphological transformation of human keratinocytes expressing the LMP gene of Epstein–Barr virus. Nature345(6274),447–449 (1990).▪ A key study in establishing the role of LMP1 in the transformation of epithelial cells.
    • Dawson CW, Rickinson AB, Young LS: Epstein–Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature344(6268),777–780 (1990).▪ Another key report highlighting the profound effects of LMP1 expression in epithelial cells in culture.
    • 10  Stevenson D, Charalambous C, Wilson JB: Epstein–Barr virus latent membrane protein 1 (CAO) upregulates VEGF and TGF α concomitant with hyperlasia, with subsequent up-regulation of p16 and MMP9. Cancer Res.65(19),8826–8835 (2005).
    • 11  Brooks L, Yao QY, Rickinson AB, Young LS: Epstein–Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol.66(5),2689–2697 (1992).
    • 12  Young LS, Dawson CW, Clark D et al.: Epstein–Barr virus gene expression in nasopharyngeal carcinoma. J. Gen. Virol.69(Part 5),1051–1065 (1988).
    • 13  Khabir A, Karray H, Rodriguez S et al.: EBV latent membrane protein 1 abundance correlates with patient age but not with metastatic behavior in north African nasopharyngeal carcinomas. Virol. J.2,39 (2005).
    • 14  Hu LF, Minarovits J, Cao SL et al.: Variable expression of latent membrane protein in nasopharyngeal carcinoma can be related to methylation status of the Epstein–Barr virus BNLF-1 5´-flanking region. J. Virol.65(3),1558–1567 (1991).
    • 15  Hu L, Troyanovsky B, Zhang X, Trivedi P, Ernberg I, Klein G: Differences in the immunogenicity of latent membrane protein 1 (LMP1) encoded by Epstein–Barr virus genomes derived from LMP1-positive and -negative nasopharyngeal carcinoma. Cancer Res.60(19),5589–5593 (2000).
    • 16  Trivedi P, Hu LF, Chen F et al.: Epstein–Barr virus (EBV)-encoded membrane protein LMP1 from a nasopharyngeal carcinoma is non-immunogenic in a murine model system, in contrast to a B cell-derived homologue. Eur. J. Cancer30A(1),84–88 (1994).
    • 17  Shao JY, Ernberg I, Biberfeld P, Heiden T, Zeng YX, Hu LF: Epstein–Barr virus LMP1 status in relation to apoptosis, p53 expression and leucocyte infiltration in nasopharyngeal carcinoma. Anticancer Res.24(4),2309–2318 (2004).
    • 18  Niedobitek G, Meru N, Delecluse HJ: Epstein–Barr virus infection and human malignancies. Int. J. Exp. Pathol.82(3),149–170 (2001).
    • 19  Hammerschmidt W, Sugden B, Baichwal VR: The transforming domain alone of the latent membrane protein of Epstein–Barr virus is toxic to cells when expressed at high levels. J. Virol.63(6),2469–2475 (1989).▪▪ Critical findings highlighting the dose-dependent effects of LMP1 expression.
    • 20  Lu JJ, Chen JY, Hsu TY, Yu WC, Su IJ, Yang CS: Induction of apoptosis in epithelial cells by Epstein–Barr virus latent membrane protein 1. J. Gen. Virol.77(Part 8),1883–1892 (1996).
    • 21  Liu Y, Wang X, Lo AK, Wong YC, Cheung AL, Tsao SW: Latent membrane protein-1 of Epstein–Barr virus inhibits cell growth and induces sensitivity to cisplatin in nasopharyngeal carcinoma cells. J. Med. Virol.66(1),63–69 (2002).
    • 22  Du C, Wen B, Li D et al.: Downregulation of Epstein–Barr virus-encoded latent membrane protein-1 by arsenic trioxide in nasopharyngeal carcinoma cells. Tumori92(2),140–148 (2006).
    • 23  Gires O, Zimber-Strobl U, Gonnella R et al.: Latent membrane protein 1 of Epstein–Barr virus mimics a constitutively active receptor molecule. EMBO J.16(20),6131–6140 (1997).
    • 24  Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E: The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell80(3),389–399 (1995).
    • 25  Eliopoulos AG, Young LS: LMP1 structure and signal transduction. Semin. Cancer Biol.11(6),435–444 (2001).
    • 26  Uchida J, Yasui T, Takaoka-Shichijo Y et al.: Mimicry of CD40 signals by Epstein–Barr virus LMP1 in B lymphocyte responses. Science286(5438),300–303 (1999).
    • 27  Aviel S, Winberg G, Massucci M, Ciechanover A: Degradation of the epstein-barr virus latent membrane protein 1 (LMP1) by the ubiquitin-proteasome pathway. Targeting via ubiquitination of the N-terminal residue. J. Biol. Chem.275(31),23491–23499 (2000).
    • 28  Lo AK, To KF, Lo KW et al.: Modulation of LMP1 protein expression by EBV-encoded microRNAs. Proc. Natl. Acad. Sci. USA104(41),16164–16169 (2007).▪▪ Very interesting report highlighting a novel level of regulation of LMP1 expression.
    • 29  Kaykas A, Worringer K, Sugden B: LMP-1’s transmembrane domains encode multiple functions required for LMP-1’s efficient signaling. J. Virol.76(22),11551–11560 (2002).
    • 30  Puls A, Eliopoulos AG, Nobes CD, Bridges T, Young LS, Hall A: Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(α) and IL-1, and by the Epstein–Barr virus transforming protein LMP1. J. Cell Sci.112(Part 17),2983–2992 (1999).
    • 31  Eliopoulos AG, Stack M, Dawson CW et al.: Epstein–Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-κB pathway involving TNF receptor-associated factors. Oncogene14(24),2899–2916 (1997).
    • 32  Izumi KM, Kieff ED: The Epstein–Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-κB. Proc. Natl. Acad. Sci. USA94(23),12592–12597 (1997).
    • 33  Mainou BA, Everly DN Jr, Raab-Traub N: Epstein–Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K. Oncogene24(46),6917–6924 (2005).
    • 34  Sandberg M, Hammerschmidt W, Sugden B: Characterization of LMP-1’s association with TRAF1, TRAF2, and TRAF3. J. Virol.71(6),4649–4656 (1997).
    • 35  Eliopoulos AG, Blake SM, Floettmann JE, Rowe M, Young LS: Epstein–Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. J. Virol.73(2),1023–1035 (1999).
    • 36  Eliopoulos AG, Gallagher NJ, Blake SM, Dawson CW, Young LS: Activation of the p38 mitogen-activated protein kinase pathway by Epstein–Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J. Biol. Chem.274(23),16085–16096 (1999).
    • 37  Chung PJ, Chang YS, Liang CL, Meng CL: Negative regulation of Epstein–Barr virus latent membrane protein 1-mediated functions by the bone morphogenetic protein receptor IA-binding protein, BRAM1. J. Biol. Chem.277(42),39850–39857 (2002).
    • 38  Li HP, Chang YS: Epstein–Barr virus latent membrane protein 1: structure and functions. J. Biomed. Sci.10(5),490–504 (2003).
    • 39  Dawson CW, Tramountanis G, Eliopoulos AG, Young LS: Epstein–Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J. Biol. Chem.278(6),3694–3704 (2003).
    • 40  Dawson CW, Laverick L, Morris MA, Tramoutanis G, Young LS: Epstein–Barr virus-encoded LMP1 regulates epithelial cell motility and invasion via the ERK–MAPK pathway. J. Virol.82(7),3654–3664 (2008).
    • 41  Gires O, Kohlhuber F, Kilger E et al.: Latent membrane protein 1 of Epstein–Barr virus interacts with JAK3 and activates STAT proteins. EMBO J.18(11),3064–3073 (1999).
    • 42  Higuchi M, Kieff E, Izumi KM: The Epstein–Barr virus latent membrane protein 1 putative Janus kinase 3 (JAK3) binding domain does not mediate JAK3 association or activation in B-lymphoma or lymphoblastoid cell lines. J. Virol.76(1),455–459 (2002).
    • 43  Lo KW, To KF, Huang DP: Focus on nasopharyngeal carcinoma. Cancer Cell5(5),423–428 (2004).
    • 44  Tao Q, Chan AT: Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. Expert Rev. Mol. Med.9(12),1–24 (2007).
    • 45  Soussi T, Ishioka C, Claustres M, Béroud C: Locus-specific mutation databases: pitfalls and good practice based on the p53 experience. Nat. Rev. Cancer6(1),83–90 (2006).
    • 46  Crook T, Nicholls JM, Brooks L, O’Nions J, Allday MJ: High level expression of ΔN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? Oncogene19(30),3439–3444 (2000).
    • 47  Chu WK, Lee KC, Chow SE, Chen JK: Dual regulation of the ΔNp63 transcriptional activity by ΔNp63 in human nasopharyngeal carcinoma cell. Biochem. Biophys. Res. Commun.342(4),1356–1360 (2006).
    • 48  Guo C, Pan ZG, Li DJ et al.: The expression of p63 is associated with the differential stage in nasopharyngeal carcinoma and EBV infection. J. Transl. Med.4,23 (2006).
    • 49  Lo KW, Mok CH, Huang DP et al.: p53 mutation in human nasopharyngeal carcinomas. Anticancer Res.12(6B),1957–1963 (1992).
    • 50  Spruck CH 3rd, Tsai YC, Huang DP et al.: Absence of p53 gene mutations in primary nasopharyngeal carcinomas. Cancer Res.52(17),4787–4790 (1992).
    • 51  Chang KP, Hao SP, Lin SY et al.: A lack of association between p53 mutations and recurrent nasopharyngeal carcinomas refractory to radiotherapy. Laryngoscope112(11),2015–2019 (2002).
    • 52  Fries KL, Miller WE, Raab-Traub N: Epstein–Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene. J. Virol.70(12),8653–8659 (1996).
    • 53  Li L, Guo L, Tao Y et al.: Latent membrane protein 1 of Epstein–Barr virus regulates p53 phosphorylation through MAP kinases. Cancer Lett.255(2),219–231 (2007).
    • 54  Wu HC, Lu TY, Lee JJ et al.: MDM2 expression in EBV-infected nasopharyngeal carcinoma cells. Lab. Invest.84(12),1547–1556 (2004).
    • 55  Morris MA, Dawson CW, Wei W et al.: Epstein–Barr virus-encoded LMP1 induces a hyperproliferative and inflammatory gene expression programme in cultured keratinocytes. J. Gen. Virol.89(Part 11),2806–2820 (2008).
    • 56  Sheu LF, Chen A, Lee HS, Hsu HY, Yu DS: Cooperative interactions among p53, bcl-2 and Epstein–Barr virus latent membrane protein 1 in nasopharyngeal carcinoma cells. Pathol. Int.54(7),475–485 (2004).
    • 57  Man C, Rosa J, Lee LT et al.: Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. Oncogene26(21),3069–3080 (2007).
    • 58  Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP: Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat. Genet.25(3),315–319 (2000).
    • 59  Macdiarmid J, Stevenson D, Campbell DH, Wilson JB: The latent membrane protein 1 of Epstein–Barr virus and loss of the INK4a locus: paradoxes resolve to cooperation in carcinogenesis in vivo. Carcinogenesis24(7),1209–1218 (2003).
    • 60  Zheng H, Li LL, Hu DS, Deng XY, Cao Y: Role of Epstein–Barr virus encoded latent membrane protein 1 in the carcinogenesis of nasopharyngeal carcinoma. Cell. Mol. Immunol.4(3),185–196 (2007).▪▪ Excellent review of the functions of LMP1 in modulating aspects of the cell cycle.
    • 61  Everly DN Jr, Mainou BA, Raab-Traub N: The ID proteins contribute to the growth of rodent fibroblasts during LMP1-mediated transformation. Virology376(2),258–269 (2008).
    • 62  Cheung ST, Huang DP, Hui AB et al.: Nasopharyngeal carcinoma cell line (C666–1) consistently harbouring Epstein–Barr virus. Int. J. Cancer83(1),121–126 (1999).
    • 63  Mei YP, Zhou JM, Wang Y et al.: Silencing of LMP1 induces cell cycle arrest and enhances chemosensitivity through inhibition of AKT signaling pathway in EBV-positive nasopharyngeal carcinoma cells. Cell Cycle6(11),1379–1385 (2007).
    • 64  Li XP, Li G, Peng Y, Kung HF, Lin MC: Suppression of Epstein–Barr virus-encoded latent membrane protein-1 by RNA interference inhibits the metastatic potential of nasopharyngeal carcinoma cells. Biochem. Biophys. Res. Commun.315(1),212–218 (2004).
    • 65  Jin X, Song X, Li L et al.: Blockade of AP-1 activity by dominant-negative TAM67 can abrogate the oncogenic phenotype in latent membrane protein 1-positive human nasopharyngeal carcinoma. Mol. Carcinog.46(11),901–911 (2007).
    • 66  Ai MD, Li LL, Zhao XR, Wu Y, Gong JP, Cao Y: Regulation of survivin and CDK4 by Epstein–Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cell lines. Cell Res.15(10),777–784 (2005).
    • 67  Seo SY, Kim EO, Jang KL: Epstein–Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-β2 expression via DNA methylation. Cancer Lett.270(1),66–76 (2008).
    • 68  Tao Y, Song X, Deng X et al.: Nuclear accumulation of epidermal growth factor receptor and acceleration of G1/S stage by Epstein–Barr-encoded oncoprotein latent membrane protein 1. Exp. Cell Res.303(2),240–251 (2005).
    • 69  Liu B, Chen XY: [Effect of EB virus latent membrane protein 1 on mitosis control of nasopharyngeal carcinoma cell line CNE1]. Ai Zheng23(5),512–516 (2004).
    • 70  Li G, Li XP, Peng Y, Liu X, Li XH: Effect of inhibition of EBV-encoded latent membrane protein-1 by small interfering RNA on EBV-positive nasopharyngeal carcinoma cell growth. Di Yi Jun Yi Da Xue Xue Bao24(3),241–246 (2004).
    • 71  Lin X, Liu S, Luo et al.: EBV-encoded LMP1 regulates Op18/stathmin signaling pathway by cdc2 mediation in nasopharyngeal carcinoma cells. Int. J. Cancer124(5),1020–1027 (2009).
    • 72  Ding L, Li LL, Yang et al.: Epstein–Barr virus encoded latent membrane protein 1 modulates nuclear translocation of telomerase reverse transcriptase protein by activating nuclear factor-κB p65 in human nasopharyngeal carcinoma cells. Int. J. Biochem. Cell Biol.37(9),1881–1889 (2005).
    • 73  Siegler G, Meyer B, Dawson C et al.: Expression of tumor necrosis factor receptor-associated factor 1 in nasopharyngeal carcinoma: possible upregulation by Epstein–Barr virus latent membrane protein 1. Int. J. Cancer112(2),265–272 (2004).
    • 74  Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML: Interleukin-6 inhibits transforming growth factor-β-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J. Biol. Chem.274(33),23013–23019 (1999).
    • 75  Wheelock MJ, Johnson KR: Cadherins as modulators of cellular phenotype. Annu. Rev. Cell Dev. Biol.19,207–235 (2003).
    • 76  Fahraeus R, Chen W, Trivedi P, Klein G, Obrink B: Decreased expression of E-cadherin and increased invasive capacity in EBV-LMP-transfected human epithelial and murine adenocarcinoma cells. Int. J. Cancer52(5),834–838 (1992).
    • 77  Tsai CN, Tsai CL, Tse KP, Chang HY, Chang YS: The Epstein–Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc. Natl. Acad. Sci. USA99(15),10084–10089 (2002).
    • 78  Horikawa T, Yang J, Kondo S et al.: Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma. Cancer Res.67(5),1970–1978 (2007).
    • 79  Tsai CL, Li HP, Lu YJ et al.: Activation of DNA methyltransferase 1 by EBV LMP1 Involves c-Jun NH(2)-terminal kinase signaling. Cancer Res.66(24),11668–11676 (2006).
    • 80  Krishna SM, Kattoor J, Balaram P: Down regulation of adhesion protein E-cadherin in Epstein–Barr virus infected nasopharyngeal carcinomas. Cancer Biomark.1(6),271–277 (2005).
    • 81  Zhang ZW, He ZM, Zhou M, Ding W, Yu YH, Chen ZC: [Mechanism of migration in CNE2 cells promoted by EBV-LMP1]. Zhong Nan Da Xue Xue Bao Yi Xue Ban31(4),470–474 (2006).
    • 82  Shair KH, Schnegg CI, Raab-Traub N: EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration. Cancer Res.68(17),6997–7005 (2008).
    • 83  Gendler SJ: MUC1, the renaissance molecule. J. Mammary Gland Biol. Neoplasia6(3),339–353 (2001).
    • 84  Kim YS, Gum J Jr, Brockhausen I: Mucin glycoproteins in neoplasia. Glycoconj. J.13(5),693–707 (1996).
    • 85  Lee MJ, Lee HS, Kim WH, Choi Y, Yang M: Expression of mucins and cytokeratins in primary carcinomas of the digestive system. Mod. Pathol.16(5),403–410 (2003).
    • 86  Ringel J, Lohr M: The MUC gene family: their role in diagnosis and early detection of pancreatic cancer. Mol. Cancer2,9 (2003).
    • 87  Taylor-Papadimitriou J, Burchell JM, Plunkett T et al.: MUC1 and the immunobiology of cancer. J. Mammary Gland Biol. Neoplasia7(2),209–221 (2002).
    • 88  Baldus SE, Engelmann K, Hanisch FG: MUC1 and the MUCs: a family of human mucins with impact in cancer biology. Crit. Rev. Clin. Lab. Sci.41(2),189–231 (2004).
    • 89  Kondo S, Yoshizaki T, Wakisaka N et al.: MUC1 induced by Epstein–Barr virus latent membrane protein 1 causes dissociation of the cell-matrix interaction and cellular invasiveness via STAT signaling. J. Virol.81(4),1554–1562 (2007).
    • 90  Lo AK, Liu Y, Wang XH et al.: Alterations of biologic properties and gene expression in nasopharyngeal epithelial cells by the Epstein–Barr virus-encoded latent membrane protein 1. Lab. Invest.83(5),697–709 (2003).
    • 91  Liu LT, Peng JP, Chang HC, Hung WC: RECK is a target of Epstein–Barr virus latent membrane protein 1. Oncogene22(51),8263–8270 (2003).
    • 92  Kim KR, Yoshizaki T, Miyamori H et al.: Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein–Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth. Oncogene19(14),1764–1771 (2000).
    • 93  Zeng L, Liu YP, Wang H et al.: [EB virus encoded latent membrane protein 1 mediated expression of transcription factor Ets-1 in nasopharyngeal carcinoma cells]. Zhonghua Zhong Liu Za Zhi26(8),454–457 (2004).
    • 94  Kwok Fung Lo A, Liu Y, Wang X et al.: Identification of downstream target genes of latent membrane protein 1 in nasopharyngeal carcinoma cells by suppression subtractive hybridization. Biochim. Biophys. Acta1520(2),131–140 (2001).
    • 95  Yang J, Mani SA, Donaher JL et al.: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell117(7),927–939 (2004).
    • 96  Shen ZH, Chen XY, Chen J: [Impact of up-regulating Ezrin expression by Epstein–Barr virus latent membrane protein 1 on metastasis ability of nasopharyngeal carcinoma cells]. Ai Zheng27(2),165–169 (2008).
    • 97  Liu QY, Han AJ, You SY et al.: [Correlation of Epstein–Barr virus-encoded latent membrane protein 1 (LMP1) to fascin and phosphorylated Stat3 in nasopharyngeal carcinoma]. Ai Zheng27(10),1070–1076 (2008).
    • 98  Horikawa T, Sheen TS, Takeshita H, Sato H, Furukawa M, Yoshizaki T: Induction of c-Met proto-oncogene by Epstein–Barr virus latent membrane protein-1 and the correlation with cervical lymph node metastasis of nasopharyngeal carcinoma. Am. J. Pathol.159(1),27–33 (2001).
    • 99  Lukashev ME, Werb Z: ECM signalling: orchestrating cell behaviour and misbehaviour. Trends Cell Biol.8(11),437–441 (1998).
    • 100  Yoshizaki T: Promotion of metastasis in nasopharyngeal carcinoma by Epstein–Barr virus latent membrane protein-1. Histol. Histopathol.17(3),845–850 (2002).
    • 101  Gou XM, Chen Y, Chen XY, Arrand JR: [Effects of Epstein–Barr virus latent membrane protein 1(EBV-LMP1) on related factors of metastasis of nasopharyngeal carcinoma cell line CNE1]. Ai Zheng22(5),481–485 (2003).
    • 102  Yoshizaki T, Sato H, Furukawa M, Pagano JS: The expression of matrix metalloproteinase 9 is enhanced by Epstein–Barr virus latent membrane protein 1. Proc. Natl. Acad. Sci. USA95(7),3621–3626 (1998).
    • 103  Horikawa T, Yoshizaki T, Sheen TS, Lee SY, Furukawa M: Association of latent membrane protein 1 and matrix metalloproteinase 9 with metastasis in nasopharyngeal carcinoma. Cancer89(4),715–723 (2000).
    • 104  Kondo S, Wakisaka N, Schell MJ et al.: Epstein–Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: enhanced susceptibility to nasopharyngeal carcinoma. Int. J. Cancer115(3),368–376 (2005).
    • 105  Zeng L, Liu YP, Tao YG, Ai MD, Zhao XR, Cao Y: [Cross-talk between c-Jun/Ets1 involved in EB virus-encoded latent membrane protein 1 regulates expression of matrix metalloproteinase-9 in nasopharyngeal carcinoma]. Zhonghua Zhong Liu Za Zhi27(4),204–208 (2005).
    • 106  Bergers G, Brekken R, McMahon G et al.: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol.2(10),737–744 (2000).
    • 107  Murono S, Yoshizaki T, Sato H, Takeshita H, Furukawa M, Pagano JS: Aspirin inhibits tumor cell invasiveness induced by Epstein–Barr virus latent membrane protein 1 through suppression of matrix metalloproteinase-9 expression. Cancer Res.60(9),2555–2561 (2000).
    • 108  Lee DC, Chua DT, Wei WI, Sham JS, Lau AS: Induction of matrix metalloproteinases by Epstein–Barr virus latent membrane protein 1 isolated from nasopharyngeal carcinoma. Biomed. Pharmacother.61(9),520–526 (2007).
    • 109  Chang SH, Chang HC, Hung WC: Transcriptional repression of tissue inhibitor of metalloproteinase-3 by Epstein–Barr virus latent membrane protein 1 enhances invasiveness of nasopharyngeal carcinoma cells. Oral Oncol.44(9),891–897 (2008).
    • 110  Kondo S, Seo SY, Yoshizaki T et al.: EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res.66(20),9870–9877 (2006).
    • 111  Murono S, Inoue H, Tanabe T et al.: Induction of cyclooxygenase-2 by Epstein–Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells. Proc. Natl. Acad. Sci. USA98(12),6905–6910 (2001).
    • 112  Wakisaka N, Kondo S, Yoshizaki T, Murono S, Furukawa M, Pagano JS: Epstein–Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 α. Mol. Cell. Biol.24(12),5223–5234 (2004).
    • 113  Yoshizaki T, Horikawa T, Qing-Chun R et al.: Induction of interleukin-8 by Epstein–Barr virus latent membrane protein-1 and its correlation to angiogenesis in nasopharyngeal carcinoma. Clin. Cancer Res.7(7),1946–1951 (2001).
    • 114  Ren Q, Sato H, Murono S, Furukawa M, Yoshizaki T: Epstein–Barr virus (EBV) latent membrane protein 1 induces interleukin-8 through the nuclear factor-κ B signaling pathway in EBV-infected nasopharyngeal carcinoma cell line. Laryngoscope114(5),855–859 (2004).
    • 115  Tsuji A, Wakisaka N, Kondo S, Murono S, Furukawa M, Yoshizaki T: Induction of receptor for advanced glycation end products by EBV latent membrane protein 1 and its correlation with angiogenesis and cervical lymph node metastasis in nasopharyngeal carcinoma. Clin. Cancer Res.14(17),5368–5375 (2008).
    • 116  Edwards RH, Sitki-Green D, Moore DT, Raab-Traub N: Potential selection of LMP1 variants in nasopharyngeal carcinoma. J. Virol.78(2),868–881 (2004).
    • 117  Burrows JM et al.: Selection pressure-driven evolution of the Epstein–Barr virus-encoded oncogene LMP1 in virus isolates from Southeast Asia. J. Virol.78(13),7131–7137 (2004).
    • 118  Chen ML, Tsai CN, Liang CL et al.: Cloning and characterization of the latent membrane protein (LMP) of a specific Epstein–Barr virus variant derived from the nasopharyngeal carcinoma in the Taiwanese population. Oncogene7(11),2131–2140 (1992).
    • 119  Hu LF, Zabarovsky ER, Chen F et al.: Isolation and sequencing of the Epstein–Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma. J. Gen. Virol.72(Part 10),2399–2409 (1991).
    • 120  Li SN, Chang YS, Liu ST: Effect of a 10-amino acid deletion on the oncogenic activity of latent membrane protein 1 of Epstein–Barr virus. Oncogene12(10),2129–2135 (1996).
    • 121  Blake SM, Eliopoulos AG, Dawson CW, Young LS: The transmembrane domains of the EBV-encoded latent membrane protein 1 (LMP1) variant CAO regulate enhanced signalling activity. Virology282(2),278–287 (2001).
    • 122  Dawson CW, Eliopoulos AG, Blake SM, Barker R, Young LS: Identification of functional differences between prototype Epstein–Barr virus-encoded LMP1 and a nasopharyngeal carcinoma-derived LMP1 in human epithelial cells. Virology272(1),204–217 (2000).
    • 123  Fielding CA, Sandvej K, Mehl A, Brennan P, Jones M, Rowe M: Epstein–Barr virus LMP-1 natural sequence variants differ in their potential to activate cellular signaling pathways. J. Virol.75(19),9129–9141 (2001).
    • 124  Nitta T, Chiba A, Yamamoto N, Yamaoka S: Lack of cytotoxic property in a variant of Epstein–Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma. Cell Signal.16(9),1071–1081 (2004).
    • 125  Huang H, Huang PC: [Effects of two LMP1 variants on resistance of CNE1 cell strain to TGF-β1]. Ai Zheng22(12),1254–1259 (2003).
    • 126  Hadhri-Guiga B, Chiba A, Yamamoto N, Yamaoka S: Various 30 and 69 bp deletion variants of the Epstein–Barr virus LMP1 may arise by homologous recombination in nasopharyngeal carcinoma of Tunisian patients. Virus Res.115(1),24–30 (2006).
    • 127  Khanim F, Yao QY, Niedobitek G, Sihota S, Rickinson AB, Young LS: Analysis of Epstein–Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations. Blood88(9),3491–3501 (1996).
    • 128  Chang KP, Hao SP, Lin SY et al.: The 30-bp deletion of Epstein–Barr virus latent membrane protein-1 gene has no effect in nasopharyngeal carcinoma. Laryngoscope116(4),541–546 (2006).