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

• Published in: International journal of cancer Vol. 115; no. 3; pp. 368 - 376
• Main Authors: Kondo, Satoru, Wakisaka, Naohiro, Schell, Michael J., Horikawa, Toshiyuki, Sheen, Tzung‐Shiahn, Sato, Hiroshi, Furukawa, Mitsuru, Pagano, Joseph S., Yoshizaki, Tomokazu
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 20-06-2005; Wiley-Liss
• Subjects: AP1; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - virology; Ets binding site; Female; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Herpesvirus 4, Human - genetics; Humans; LMP1; Male; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 3 - genetics; Matrix Metalloproteinase 3 - metabolism; Medical sciences; Middle Aged; MMP1; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - virology; Otorhinolaryngology. Stomatology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets; SNP; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription Factors - metabolism; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; Viral Matrix Proteins - pharmacology; Asia; Japan; Taiwan; LMP1; Ets binding site; Prognosis; Genetic variability; Transcription promoter; Metalloendopeptidases; Binding site; Epstein Barr virus; Nasopharynx carcinoma; Epidemiology; Cancerology; SNP; Genetics; ENT disease; Pharynx disease; Public health; Interstitial collagenase; Gammaherpesvirinae; Human; Enzyme; MMP1; Herpesviridae; Genotype; Malignant tumor; Infection; Virus; Peptidases; Viral disease; Risk factor; Hydrolases; API; Single nucleotide polymorphism; Latent membrane protein 1
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.20849

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.