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

King Chi Chan, Josephine Mun Yee Ko, Hong Lok Lung, Radislav Sedlacek, Zeng Feng Zhang, Dian Zhong Luo, Zhen Bo Feng, Shuang Chen, Honglin Chen, Kwok Wah Chan, Sai Wah Tsao, Daniel Tsin Tien Chua, Eugene R. Zabarovsky, Eric J. Stanbridge, Maria Li Lung*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1826-1837
Number of pages12
JournalInternational Journal of Cancer
Volume129
Issue number8
DOIs
Publication statusPublished - 15 Oct 2011

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • angiogenesis
  • MMP19
  • nasopharyngeal carcinoma
  • tumor suppressor gene

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