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 journalArticle

27 Citations (Scopus)

Abstract

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
Volume202
Issue number4
DOIs
Publication statusPublished - 2004 Apr

Fingerprint

Matrix Metalloproteinase 14
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase 2
Salivary Glands
Mucoepidermoid Carcinoma
Carcinoma
Adenoid Cystic Carcinoma
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Adenocarcinoma
Neoplasm Metastasis
Matrix Metalloproteinases
Matrix Metalloproteinase 13
Enzyme Precursors
Gelatin
Immunoenzyme Techniques
Extracellular Matrix
Lymph Nodes

Keywords

  • 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

Cite this

Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas : Possible regulation of pro-MMP-2 activation by TIMP-2. / Kayano, Kaori; Shimada, Taketoshi; Shinomiya, Takashi; Nakai, Shigeru; Hisa, Yasuo; Aoki, Takanori; Seiki, Motoharu; Okada, Yasunori.

In: Journal of Pathology, Vol. 202, No. 4, 04.2004, p. 403-411.

Research output: Contribution to journalArticle

Kayano, K, Shimada, T, Shinomiya, T, Nakai, S, Hisa, Y, Aoki, T, Seiki, M & Okada, Y 2004, 'Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas: Possible regulation of pro-MMP-2 activation by TIMP-2', Journal of Pathology, vol. 202, no. 4, pp. 403-411. https://doi.org/10.1002/path.1541
Kayano, Kaori ; Shimada, Taketoshi ; Shinomiya, Takashi ; Nakai, Shigeru ; Hisa, Yasuo ; Aoki, Takanori ; Seiki, Motoharu ; Okada, Yasunori. / Activation of pro-MMP-2 mediated by MT1-MMP in human salivary gland carcinomas : Possible regulation of pro-MMP-2 activation by TIMP-2. In: Journal of Pathology. 2004 ; Vol. 202, No. 4. pp. 403-411.
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