Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas: Possible regulation of pro-MMP-2 activation by TIMP-2

Kaori Kayano, Taketoshi Shimada, Takashi Shinomiya, Shigeru Nakai, Yasuo Hisa, Takanori Aoki, Motoharu Seiki, Yasunori Okada

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


Matrix metalloproteinases (MMPs), a family of extracellular matrix-degrading enzymes, are considered to play important roles in cancer invasion and metastasis. The present study examined the production levels of eight different MMPs (MMP-1, 2, 3, 7, 8, 9 and 13, and MT1-MMP) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in homogenates of human salivary gland carcinomas [mucoepidermoid carcinomas (MECs), adenoid cystic carcinomas (ACCs), and adenocarcinomas (ADEs)] and non-neoplastic control salivary glands using sandwich enzyme immunoassay systems. The levels of MMP-1, MMP-2, MMP-13, MT1-MMP, and TIMP-1 were significantly higher in the carcinoma samples than in the controls (p < 0.05). Gelatin zymography demonstrated that the activation ratio of the MMP-2 zymogen (pro-MMP-2) was significantly higher in the carcinomas than in the controls (p < 0.05). In addition, the activation ratio in MECs was significantly higher than that in ACCs or ADEs (p < 0.01) and also correlated with histological grade and lymph node metastasis in MECs (p < 0.05), whereas the ratio showed no such correlation in ACCs or ADEs. Although the production levels of pro-MMP-2 and MT1-MMP were similar among these carcinoma groups, TIMP-2 levels were significantly higher in ACCs and ADEs than in MECs (p < 0.01). In carcinoma samples, the pro-MMP-2 activation ratio correlated directly with the MT1-MMP/TIMP-2 ratio (r = 0.736, n = 23; p < 0.01). Immunohistochemistry and in situ zymography demonstrated localization of MMP-2, MT1-MMP, and TIMP-2 to carcinoma cells, but only in MECs did carcinoma cell nests exhibit gelatinolytic activity, which was inhibited by 1,10-phenanthroline. These results suggest that enhanced activation of pro-MMP-2 mediated by MT1-MMP is implicated in the invasion and metastasis of MECs and that TIMP-2 may regulate pro-MMP-2 activation in salivary gland carcinomas.

Original languageEnglish
Pages (from-to)403-411
Number of pages9
JournalJournal of Pathology
Issue number4
Publication statusPublished - 2004 Apr


  • Activation of pro-MMP-2
  • Adenocarcinoma
  • Adenoid cystic carcinoma
  • MMP
  • MT1-MMP
  • Mucoepidermoid carcinoma
  • Salivary gland
  • TIMP-2

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


Dive into the research topics of 'Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas: Possible regulation of pro-MMP-2 activation by TIMP-2'. Together they form a unique fingerprint.

Cite this