Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: Implications for lymph node metastasis

Authors: Shimada, Taketoshi¹; Nakamura, Hiroyuki²; Yamashita, Kaname¹; Kawata, Ryo³; Murakami, Yasushi³; Fujimoto, Noboru⁴; Sato, Hiroshi⁵; Seiki, Motoharu⁶; Okada, Yasunori²

Source: Clinical and Experimental Metastasis, Volume 18, Number 2, March 2000 , pp. 179-188(10)

Publisher: Springer

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Abstract:

We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2, 3, 8, 9, 13 and TIMP-1 were significantly higher in the carcinoma samples than in the control. Among them, only the production level of MMP-2 was significantly higher in the carcinomas with cervical lymph node metastasis than in those without metastasis (P<0.05). Gelatin zymography demonstrated that activation ratio of the zymogen of MMP-2 (proMMP-2) is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P<0.05) or normal control (P<0.01). Quantitative RT-PCR for membrane-types 1, 2 and 3 MMPs (MT1, 2 and 3-MMPs), which activate proMMP-2 in vitro, demonstrated that MT1-MMP is predominantly expressed in the carcinoma tissues, and the expression level is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P<0.05) or the control samples (P<0.05). Although MT2-MMP and MT3-MMP were detected in approximately 30% of the carcinoma cases, their expression levels were extremely lower compared with that of MT1-MMP. There was a direct correlation between the MT1-MMP expression level and proMMP-2 activation ratio (r=0.62, P<0.01). In situ hybridization and immunohistochemistry indicated that carcinoma cells and stromal cells adjacent to carcinoma cell nests express MT1-MMP transcripts and protein. MMP-2 and TIMP-2 were also immunolocalized to the carcinoma cells in the carcinoma samples. By in situ zymography, gelatinolytic activity was demonstrated in the carcinoma cell nests and abolished by the treatment with an MMP inhibitor, BB94. These results suggest that among seven different MMPs, the production of proMMP-2 and its activation mediated by MT1-MMP play an important role in the cervical lymph node metastasis of the human oral squamous cell carcinomas.

Keywords: activation of proMMP-2; lymph node metastasis; matrix metalloproteinase; membrane-type matrix metalloproteinase; oral squamous cell carcinoma; tissue inhibitor of metalloproteinases

Document Type: Research article

DOI: 10.1023/A:1006749501682

Affiliations: 1: Departments of Molecular Immunology and Pathology, Cancer Research Institute, 011011011011011011011011Kanazawa University, Kanazawa, 011011011011011011011011011920-0934, 2: Department of Pathology, School of Medicine, 011011011011011011011011Keio University, Tokyo , 011011011011011011011011011160-0016, 011011011011011011011011011Japan, 3: Department of Otolaryngology, 011011011011011011011011Kyoto Prefectural University of Medicine, Kyoto , 011011011011011011011011011602-0841, 011011011011011011011011011Japan, 4: Biopharmaceutical Department, 011011011011011011011011Fuji Chemical Industries, Ltd., Takaoka , 011011011011011011011011011933-8511, 011011011011011011011011011Japan, 5: Molecular Virology, Cancer Research Institute, 011011011011011011011011Kanazawa University, Kanazawa, 011011011011011011011011011920-0934, 011011011011011011011011011Japan, 6: Department of Cancer Cell Research, Institute of Medical Science, 011011011011011011011011University of Tokyo, Tokyo , 011011011011011011011011011108-0071, 011011011011011011011011011Japan,

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