Abstract 3069: Importance of zinc-binding domain of matrix metalloproteinase 19 (MMP19) in tumor suppression and anti-angiogenesis of nasopharyngeal carcinoma

Abstract

Abstract Background and aims: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases consisting of more than 20 enzymes. MMP19 shares the typical MMP structural domains. It degrades various ECM components including collagen type IV, nidogen-1, fibronectin, tenascin-C isoform, aggrecan, and laminin-5-gamma-2-chain. In our previous studies, MMP19 was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC). It was down-regulated in NPC cell lines and NPC biopsies, when compared to an immortalized normal nasopharyngeal epithelial cell line and corresponding non-tumor nasopharyngeal tissues. Transfection of wild-type (WT) MMP19 into the HONE1-2 NPC cell line significantly suppressed tumor formation in the nude mouse tumorigenicity assay and decreased the tube-forming ability of both human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1). In this study, we aimed to validate the importance of the zinc-binding domain of MMP19 in NPC. Methods: We transfected the mutant MMP19, which contained a mutation at the zinc-binding domain, into HONE1-2 to study the effect of mutant MMP19 in tumor suppression and anti-angiogenesis compared to WT MMP19. Results: Mutant MMP19 was not tumor-suppressive, as is the WT MMP19, and aggressive tumors appeared with the same growth kinetics as the vector-alone control. The anti-angiogenesis effect was also not observed in endothelial cells incubated with conditioned medium from mutant MMP19 clones compared to WT MMP19 clones. Conclusions: Previous studies showed mutation of the zinc-binding domain in MMP19 leads to loss of MMP19 function in cell proliferation, migration, and protein degradation in a human keratinocyte cell model. This study demonstrates loss of tumor suppressive and anti-angiogenesis function of mutant MMP19 in NPC and indicates the importance of the zinc-binding motif for WT MMP19 in suppression of tumor formation and in inhibition of tube-forming ability of endothelial cells in NPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3069.