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

Open Access
Publisher Website
Google Scholar
Abstract
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 this2Ginsertion type on NPC. We genotyped 44 Japanese and 39 Taiwanese NPC patients, as well as 58 Japanese and 23 Taiwanese healthy controls. The proportion of2Ghomozygotes 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 the1G/1Ggenotype disclosed a favorable prognosis (5‐year survival rate = 100%,p= 0.04). Multivariate analysis showed that1G/1Ghas independent prognostic significance. We also examined whether LMP1 enhances MMP1 expression in epithelial cells in culture. LMP1‐transfected cells with2G/2Ggenotype 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 by2G, which is a candidate marker for both risk and prognosis of NPC.