國家衛生研究院 NHRI:Item 3990099045/6438
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    題名: Epstein-Barr virus latent membrane protein 2A promotes invasion of nasopharyngeal carcinoma cells through ERK/Fra-1-mediated induction of matrix metalloproteinase 9
    作者: Lan, YY;Hsiao, JR;Chang, KC;Chang, JSM;Chen, CW;Lai, HC;Wu, SY;Yeh, TH;Chang, FH;Lin, WH;Su, IJ;Chang, Y
    貢獻者: Division of Infectious Diseases;National Institute of Cancer Research
    摘要: Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is highly metastatic and this malignant feature may be promoted by an EBV oncoprotein, latent membrane protein (LMP)-2A. Acting as a signal regulator, LMP2A can enhance invasiveness and motility of epithelial cells. It is largely unknown, downstream from the LMP2A-triggered signaling events, what key effector proteins are induced and essentially promote cell invasion. In the present study, we found that, in NPC cells, LMP2A upregulated matrix metalloproteinase 9 (MMP9), a metastasis-associated protease. LMP2A increased MMP9 expression at both the mRNA and protein levels. It also activated the MMP9 promoter, in which two AP-1 elements were required for the promoter activation. Among AP-1 transcription factors, Fra-1 was induced by LMP2A and essential for the LMP2A-triggered MMP9 expression. Induction of Fra-1 was dependent on the LMP2A-activated ERK1/2 pathway, and induction of the ERK1/2-Fra-1-MMP9 axis required PY motifs in the amino-terminal domain of LMP2A. Notably, LMP2A-promoted invasion of NPC cells was blocked when MMP9 expression, Fra-1 induction, or ERK1/2 activation was inhibited. In addition, we found an association of LMP2A with MMP9 expression in NPC tumor biopsies, where Fra-1 was a major mediation factor. This study reveals an underlying mechanism of LMP2A-induced cell invasion, from signal transduction to upregulation of a critical protease. Considering MMP9 can be also upregulated by another EBV oncoprotein LMP1, this protease may be a pivotal effector at which the EBV-induced, invasion-promoting mechanisms converge, serving as an attractive therapeutic target for NPC treatment.
    日期: 2012-06
    關聯: Journal of Virology. 2012 Jun;86(12):6656-6667.
    Link to: http://dx.doi.org/10.1128/jvi.00174-12
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-538X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000304894100026
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84864007453
    顯示於類別:[張堯] 期刊論文
    [蘇益仁(2002-2015)] 期刊論文
    [張書銘] 期刊論文

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