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Catalytic activity of matrix metalloproteinase‐19 is essential for tumor suppressor and anti‐angiogenic activities in nasopharyngeal carcinoma
Author(s) -
Chan King Chi,
Ko Josephine Mun Yee,
Lung Hong Lok,
Sedlacek Radislav,
Zhang ZengFeng,
Luo DianZhong,
Feng ZhenBo,
Chen Shuang,
Chen Honglin,
Chan Kwok Wah,
Tsao Sai Wah,
Chua Daniel Tsintien,
Zabarovsky Eugene R.,
Stanbridge Eric J.,
Lung Maria Li
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25855
Subject(s) - nasopharyngeal carcinoma , microbiology and biotechnology , angiogenesis , biology , cell culture , vascular endothelial growth factor , cancer research , umbilical vein , in vitro , biochemistry , medicine , genetics , vegf receptors , radiation therapy
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.