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Carcinogenesis Advance Access originally published online on May 29, 2009
Carcinogenesis 2009 30(8):1443-1451; doi:10.1093/carcin/bgp135
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Decoy receptor 3, upregulated by Epstein-Barr virus latent membrane protein 1, enhances nasopharyngeal carcinoma cell migration and invasion

Cheng-Hsun Ho1, Chi-Long Chen2,3, Wing-Yin Li4 and Chi-Ju Chen1,*

1 Institute of Microbiology and Immunology, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 112, Taiwan
2 Department of Pathology, Taipei Medical University, Taipei 110, Taiwan
3 Department of Pathology, Taipei Municipal Wangfang Hospital, Taipei 116, Taiwan
4 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan

* To whom correspondence should be addressed. Room 408, Institute of Microbiology and Immunology, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 112, Taiwan. Tel: +886 2 2826 7180; Fax: +886 2 2821 2880; Email: cjchen{at}ym.edu.tw

Decoy receptor 3 (DcR3), a member of tumor necrosis factor receptor superfamily, has been implicated in tumorigenesis through its abilities to modulate immune responses and induce angiogenesis. Epstein-Barr virus (EBV), a ubiquitous {gamma}-herpesvirus, is associated with malignancies including nasopharyngeal carcinoma (NPC). Previous studies show that DcR3 is overexpressed in EBV-positive lymphomas and Rta, an EBV transcription activator, can upregulate DcR3 in Burkitt lymphoma cell lines. However, DcR3 expression has not been demonstrated in EBV-associated NPC nor have there been any EBV latent genes linked to DcR3 upregulation. Here, we showed DcR3 was overexpressed in NPC. Higher DcR3 expression score and DcR3-positive rate were found in metastatic NPC than in primary NPC tissues, suggesting DcR3 may enhance cell metastatic potential. This hypothesis is supported by our observation that NPC HONE-1 cells overexpressing DcR3 exhibited significant higher migration and invasion abilities in vitro. We found besides Rta, EBV latent membrane protein (LMP) 1 can upregulate DcR3 via nuclear factor-kappaB and phosphatidylinositol 3-kinase-signaling events. Approximate 75% of LMP1-positive NPC tissues overexpressed DcR3, suggesting LMP1 may enhance DcR3 expression in vivo. Data herein suggested that increasing DcR3 expression by LMP1 not only helps EBV-associated cancer cells gain survival advantage by preventing host immune detection but also increases the chance of cancer metastasis by enhancing cell migration and invasion. All these DcR3-mediated events facilitate normal cells to gain cancer hallmarks.

Abbreviations: CTAR, C-terminal activation region; DcR3, Decoy receptor 3; EBER, EBV-encoded RNA; EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular-regulated kinase; IHC, immunohistochemistry; JNK, c-Jun N-terminal kinase; LCL, lymphoblastoid cell line; LMP, latent membrane protein; MAPK, mitogen-activated protein kinase; NF-{kappa}B, nuclear factor-kappaB; NPC, nasopharyngeal carcinoma; PI3K, phosphatidylinositol 3-kinase; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor

Received January 15, 2009; revised May 20, 2009; accepted May 23, 2009.


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