Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma

Abstract

The association of Matrix metalloproteinase-19 (MMP19) in the development of nasopharyngeal carcinoma (NPC) was identified from differential gene profiling, which showed MMP19 was one of the candidate genes down-regulated in the NPC cell lines. In this study, quantitative RT-PCR and Western blot analysis showed MMP19 was down-regulated in all seven NPC cell lines. By tissue microarray immunohistochemical staining, MMP19 appears down-regulated in 69.7% of primary NPC specimens. Allelic deletion and promoter hypermethylation contribute to MMP19 down-regulation. We also clearly demonstrate that the catalytic activity of MMP19 plays an important role in antitumor and antiangiogenesis activities in comparative studies of the wild-type and the catalytically inactive mutant MMP19. In the in vivo tumorigenicity assay, only the wild-type (WT), but not mutant, MMP19 transfectants suppress tumor formation in nude mice. In the in vitro colony formation assay, WT MMP19 dramatically reduces colony-forming ability of NPC cell lines, when compared to the inactive mutant. In the tube formation assay of human umbilical vein endothelial cells and human microvascular endothelial cells (HMEC-1), secreted WT MMP19, but not mutant MMP19, induces reduction of tube-forming ability in endothelial cells with decreased vascular endothelial growth factor (VEGF) in conditioned media detected by enzyme-linked immunosorbent assay (ELISA). The anti-angiogenic activity of WT MMP19 is correlated with suppression of tumor formation. These results now clearly show that catalytic activity of MMP19 is essential for its tumor suppressive and anti-angiogenic functions in NPC.Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelial cells of the nasopharynx. This cancer has a unique racial and geographic distribution with a high incidence in Southern China and Southeast Asia among the Southern Chinese population. 1 The etiology of NPC is believed to be multifactorial including dietary and

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In particular, tumors from the central nervous system, such as glioma, display a diffuse MMP-19 expression which further correlates with an advanced state and invasiveness of the tumor (Brauer et al, 2011;Chan et al, 2011;Velinov et al, 2007). Nonetheless, MMP-19 quantification has become a WHO-accepted value for human glioma stadiation (Lettau et al, 2010;Müller et al, 2010;Stojic et al, 2008).…”

Epigenetic disruption of cell signaling in nasopharyngeal carcinoma

“…MMP19 expression was down-regulated in ∼70% of primary NPC due to allelic deletion and promoter CpG methylation, whereas the catalytic activity of MMP-19 showed anti-tumor and anti-angiogenesis activities in NPC through decreasing vascular endothelial growth factor (VEGF) level[45]. Thus, disturbance of cell adhesion signaling molecules by aberrant methylation promotes tumor invasion and metastasis during NPC tumorigenesis [10],[46],[47].…”

Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation

“…The cells were viewed under a light microscope (IX53, OLYMPUS, Japan); the images of the capillary network were acquired, and total tube lengths formed were measured using the ImageJ software (National Institutes of Health, MD, USA). Tube formation assays were performed in triplicate, and 2 independent experiments were conducted [17].…”