Molecular mechanism for cell-cell adhesion in canceration and metastasis

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More than 90% of malignant tumors are derived from the epithelium. Thus, in this project, we focused on the analyses of tight junctions and ERM proteins to clarify the nature of the. epithelium. Major results are as follows:1. Claudin-1-deficient mice were generated. Their epidermal barrier was affected, and the proliferation of epidermal cells appeared to be abnormal.2. Claudin-5-deficient mice were generated. Their blood-brain barrier was affected in a size-dependent manner. This finding was intriguing from the viewpoint of drug deliver to the brain tumors.3. The dynamic behavior of claudin-based tight junction strands was successfully observed in live cells. Their behavior was more dynamic than ever expected.4. Snail, a transcription factor, plays a key role in the epithelial-mesenchymal transition, which is important in the metastasis of cancer cells. We found that Snail completely repressed the transcription of occludin and claudins through its direct binding to the E-boxes of the promoter regions of these genes.5. Claudin-1 was shown to be overexpressed in human colon cancer (in collaboration with Prof. Nakamura's group).6. We established the system, in which a certain gene can be double-knocked out in cultured epithelial cells. With this system, an epithelial cell line lacking the expression of ZO-1 and ZO-2 was established.7. The structure of the gene product of NF2, an ERM-like tumor suppressor gene, was clarified by X-ray diffraction analyses (in collaboration with Prof.Hakozaki's group).