Tight Junction Protein Claudin-1 Enhances the Invasive Activity of Oral Squamous Cell Carcinoma Cells by Promoting Cleavage of Laminin-5 Gamma2 Chain Via Matrix Metalloproteinase (Mmp)-2 and Membrane-type Mmp-1.
From: Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi, Japan. nao_sachi228@yahoo.co.jp
Cancer research
- Publish Date: May 2006
- ISSN: 0008-5472
- Volume: 66
- Issue: 10
- Pages: 5251-7
- Medium: Print
- Language: English
- Citation (JAMA): Oku Naohisa, Sasabe Eri, Ueta Eisaku, et al. Tight Junction Protein Claudin-1 Enhances the Invasive Activity of Oral Squamous Cell Carcinoma Cells by Promoting Cleavage of Laminin-5 Gamma2 Chain Via Matrix Metalloproteinase (Mmp)-2 and Membrane-type Mmp-1.. Cancer Res. May 2006;66:5251-7
Abstract
Although adherent junctions have been extensively studied, the role of tight junctions in cancer cell invasion is not sufficiently explored. We investigated whether claudin-1, a component of tight junctions, regulated invasion activity in oral squamous cell carcinoma (OSC) cells. The expression of claudin-1, activity of matrix metalloproteinase (MMP)-2, and cleavage of laminin-5 gamma2 chains were assessed by Western blot analysis, immunohistochemistry, and zymography in OSC cell lines (OSC-4 and NOS-2, highly invasive; OSC-7, weakly invasive) and their xenografts in severe combined immunodeficient (SCID) mice. The influence of claudin-1 small interfering RNA (siRNA) on the invasion activity of the cell lines was also investigated. Compared with OSC-7, both OSC-4 and NOS-2 more strongly expressed claudin-1 and possessed high activities of MMP-2 and MMP-9. Tumors formed in the tongues of SCID mice xenografted with OSC-4, NOS-2, and OSC-7 immunohistochemically revealed strong, moderate, and weak expression of laminin-5 gamma2 chains, respectively, and laminin-5 gamma2 chains were secreted in the conditioned medium of the cancer cells in parallel with the in vivo results. Claudin-1 siRNA largely suppressed the invasion of OSC-4 and decreased the activation of MMP-2, the expression of membrane-type MMP-1 (MT1-MMP), and the cleavage of laminin-5 gamma2. In addition, not only antibodies against MT1-MMP and epidermal growth factor receptor (EGFR) but also MMP-2 and EGFR inhibitors strongly suppressed the invasion activity of OSC-4. These results suggest that claudin-1 up-regulates cancer cell invasion activity through activation of MT1-MMP and MMP-2, which results in enhanced cleavage of laminin-5 gamma2 chains.
Mesh Headings (Keywords): Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Humans, Immunohistochemistry, Laminin, Male, Matrix Metalloproteinase 14, Matrix Metalloproteinase 2, Matrix Metalloproteinases, Matrix Metalloproteinases, Membrane-Associated, Membrane Proteins, Mice, Mice, SCID, Mouth Neoplasms, Neoplasm Invasiveness, Neoplasm Transplantation, RNA, Small Interfering, Tongue Neoplasms, Transcription Factors, Transplantation, Heterologous, Up-Regulation
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