title: 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.
authors.affiliation: Department of Clinical Oncology and Centre for Cancer Research, University of Hong Kong, Pokfulam, Hong Kong (SAR), People's Republic of China.
authors.forename: King Chi
authors.initials: KC
authors.lastname: Chan
authors.forename: Josephine Mun Yee
authors.initials: JM
authors.lastname: Ko
authors.forename: Hong Lok
authors.initials: HL
authors.lastname: Lung
authors.forename: Radislav
authors.initials: R
authors.lastname: Sedlacek
authors.forename: Zeng-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Dian-Zhong
authors.initials: DZ
authors.lastname: Luo
authors.forename: Zhen-Bo
authors.initials: ZB
authors.lastname: Feng
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Daniel Tsin-Tien
authors.initials: DT
authors.lastname: Chua
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Zabarovsky
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Stanbridge
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D002277:Carcinoma; D002384:Catalysis; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D019656:Loss of Heterozygosity; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D020533:Angiogenesis Inhibitors; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19