The expression of matrix metalloproteinase 9 is enhanced by Epstein–Barr virus latent membrane protein 1

The Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1) has a significant role in several malignancies, including nasopharyngeal carcinoma (NPC). LMP1 is the principal oncoprotein, and we have shown that it also induces a set of factors that mediates invasion, angiogenesis and metastasis. Matrix metalloproteinase-1 (MMP1) is also involved in several malignancies. A single guanine insertion polymorphism (2G) in the MMP1 promoter creates an Ets binding site that causes high levels of transcription and correlates with risk for some malignancies. Here, we evaluate the impact of this 2G insertion type on NPC. We genotyped 44 Japanese and 39 Taiwanese NPC patients, as well as 58 Japanese and 23 Taiwanese healthy controls. The proportion of 2G homozygotes was higher in the NPC groups than in controls (Japanese: p = 0.02, odds ratio (OR) = 2.49; Taiwanese: p = 0.02, OR = 3.66). An analysis of overall survival rates in the patients with NPC, and the 1G/1G genotype disclosed a favorable prognosis (5-year survival rate = 100%, p = 0.04). Multivariate analysis showed that 1G/1G has independent prognostic significance. We also examined whether LMP1 enhances MMP1 expression in epithelial cells in culture. LMP1-transfected cells with 2G/2G genotype expressed MMP1, which was abolished by activator protein-1 (AP1) dominant-negative (DN) and Ets-DN. LMP1 also induced active MMP3, which can cleave latent MMP1, and AP1-DN and Ets-DN suppressed the MMP3 expression. These results suggest that LMP1-induced MMP1 and MMP3 are closely linked and show that LMP1 activates MMP1 via an Ets binding site formed by 2G, which is a candidate marker for both risk and prognosis of NPC. ' 2005 Wiley-Liss, Inc.Key words: SNP; MMP1; LMP1; Ets binding site; AP1EBV is a human herpes virus associated with an increasing number of malignancies, both lymphoid and epithelial in origin, including Burkitt's lymphoma and nasopharyngeal carcinoma (NPC). 1-3 Among the viral proteins expressed in the transformed cells, the nuclear antigens, Epstein-Barr nuclear antigen 2 (EBNA2), EBNA3A, EBNA3c and the integral membrane protein called latent membrane protein 1 (LMP1) are essential for growth transformation and immortalization of resting B lymphocytes. 4,5 The carboxyl-terminal portion of LMP1, which is in the cytoplasmic domain of the protein, contains 2 functional domains. The proximal domain, COOH-terminal activation region 1 (CTAR1), interacts with tumor necrosis factor receptor-associated factors and induces nuclear factor-kB (NF-kB). 6,7 The distal domain, CTAR2, is the dominant NF-kB and c-Jun N-terminal kinase (JNK) activating region of LMP1. 8,9 Previously, we showed that the CTAR1 domain also induces Ets1, a member of the Ets transcription family, and recognizes specific nucleotides sequences with a GGAA/T core sequence. We also showed that LMP1 induces c-Met, which enhances cell motility, via Ets1. [10][11][12] We have shown that LMP1 induces MMP9, a type IV collagenase that is a key enzyme in metastasis and cell invasion. 12-15 However, MMP9 is un...

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“…[13][14][15] MMP1 should contribute to tumor progression in NPC by means of its ability to destroy interstitial collagens.…”

Section: Discussionmentioning

confidence: 99%

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

Kondo

Wakisaka

Schell

et al. 2005

Intl Journal of Cancer

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“…Previously, we reported that LMP1 stimulated expression of matrix metalloproteinase-9 (MMP-9), which is implicated in tumor invasion and metastasis by degrading type IV collagen, a major component of basement membrane (Yoshizaki et al, 1998;Takeshita et al, 1999). Expression of MMP-9 gene was at a very high level in parental MDCK cells and was not further stimulated by transformation with LMP1 (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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“…When the authors could not find any vessel structure highlighted in the tumor stroma, the specimen was considered A pcDNA3-based LMP1-expression plasmid (pcLMP1) has been described previously [23] . Ad-AH cells are an EBV-negative human nasopharyngeal epithelial cell line [24] .…”

Section: Introductionmentioning

confidence: 99%

Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma

et al. 2012

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Objectives: The contribution of the lymphatic system to tumor metastasis is being increasingly appreciated through studies of human cancers. As the biological behavior of nasopharyngeal carcinoma (NPC) depends on its nodal status, patients with advanced nodal status show a higher tendency toward a poor outcome. Here, we examined the role of lymphangiogenesis on lymphatic spread of NPC. We also evaluated

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The expression of matrix metalloproteinase 9 is enhanced by Epstein–Barr virus latent membrane protein 1

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Cited by 210 publications

References 58 publications

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

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

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

Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma

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