| Co-Investigator(Kenkyū-buntansha) |
ESTEBAN Gabazza Mie University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (00293770)
KAMADA Haruhiko Mie University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (00324509)
HAYASHI Tatsuya Mie University, Faculty of Medicine, Lecturer, 医学部, 講師 (00242959)
WADA Hideo Mie University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (40158704)
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| Research Abstract |
Protein C inhibitor (PCI), a member of the SERPIN family, is produced in various human tissues, including the liver, kidney, and testis. In addition to inhibit the anticoagulant protein C pathway, PCI also inhibits urinary uPA, which is a well-known mediator of tumor cell invasion. (1) To clarify the biological significance of PCI in the kidney, we compared the expression of PCI between human renal cell carcinoma (RCC) tissue and non-tumor kidney tissue. The PCI level in RCC tissue was found to be significantly lower than in non-tumor kidney tissue, and expression of PCI mRNA was detected in normal renal proximal tubular epithelial cells, but not in RCC nor in an RCC cell line (Caki-1cells). Methylation of some CpG islands in the promoter region of PCI gene was detected from RCC cell lines, but not from non-tumor kidney cells. The in vitro invasiveness of Caki-1 cells transfected with a PCI expression vector was significantly decreased compared to mock-transfected Caki-1 cells. These f
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indings suggest that PCI regulates the invasive potential of RCC cells by inhibiting uPA secreted by these cells. (2) Moreover, we produced human PCI gene-transgenic (TG) mice and characterized the tissue distribution and biological functions of PCI expressed in the TG mice. Northern blot and immunohistochemical analyses showed that in the TG mice the human PCI is expressed not only in the reproductive organs such as testis, ovary and uterus, but also in the liver hepatocytes, renal epithelial cells, heart and brain; these tissue distribution of the PCI being similar to that in humans. The PCI expressed in the TG mice efficiently inhibited the anticoagulant and anti-inflammatory activities of the extraneously injected human activated protein C (APC) in the TG mice by forming a complex with APC. These findings demonstrate that human PCI gene TG mice are useful as experimental animal models to evaluate pathological significance of human PCI and also therapeutic effects of human APC in vivo. Less
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