2005 Fiscal Year Final Research Report Summary
Attempt of suppression of oral cancer invasion by overexpression of tight and adherens junction constitution proteins
| Project/Area Number |
16591886
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathobiological dentistry/Dental radiology
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| Research Institution | Kochi University |
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Principal Investigator |
OKU Naohisa Kochi University, Oral Oncology, Research Associate, 医学部附属病院, 助手 (20363286)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Tetsuya Kochi University, Oral Oncology, Professor, 医学部, 教授 (00200824)
UETA Eisaku Kochi University, Oral Oncology, Lecturer, 医学部附属病院, 講師 (10203431)
KAMATANI Takaaki Kochi University, Oral Oncology, Research Associate, 医学部附属病院, 助手 (00315003)
SASABE Eri Kochi University, Oral Oncology, Research Associate, 医学部附属病院, 助手 (40363288)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Tight junction / Claudin-1 / Laminin-5 γ2 chain / Invasion / Metastasis |
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| Research 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 (TJs), 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 (Ln-5). γ2 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 SCID (severe combined immunodeficient) mice. The influence of claudin-1 siRNA on the invasion activity of the cell lines was also investigated. Compared to OSC-7, both OSC-4 and NOS-2 more strongly expressed claudin-1 and possessed high activities of MMP-2 and -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 Ln-5 γ2 chains, respectively, and Ln-5 γ2 chains were secreted in the conditioned media of the cancer cells in parallel with the in vivo results. Claudin-1 siRNA largely suppressed the invasion of OSC-4, and claudin-1 siRNA decreased the activation of MMP-2, the expression of membrane-type MMP-1 (MT1-MMP) and the cleavage of Ln-5 γ2. In addition, not only antibodies against MT1-MMP and epidermal growth factor receptor (EGF-R) but also MMP-2 and EGF-R 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 Ln-5 γ2 chains.
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