| Project/Area Number |
11671607
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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 |
Obstetrics and gynecology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
KOBAYASHI Hiroshi Hamamatsu Univ. Sch. Of Med., Obstet. Gynecol., Assistant Prof., 医学部附属病院, 講師 (40178330)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Mitsuaki Jichi Med. Univ., Obstet. Gynecol., Prof., 医学部, 教授 (50110870)
OOI Hidekazu Hamamatsu Univ. Sch. Of Med., Obstet. Gynecol., Assistant, 医学部附属病院, 助手 (10283368)
NISHIGUCHI Tomizo Hamamatsu Univ. Sch. Of Med., Obstet. Gynecol., Assistant Prof., 医学部附属病院, 講師 (30198452)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Metastasis / Anti-metastatic agent / Cancer Invasion / Gene therapy |
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| Research Abstract |
Bikunin (bik), a Kunitz-type protease inhibitor, also known as urinary trypsin inhibitor, is proposed as a main participant in the inhibition of tumor cell invasion and metastasis, possibly through the direct inhibition of cell-associated plasmin activity and suppression of urokinase-type plasminogen activator (uPA) mRNA expression. In the present study, we transfected the human ovarian carcinoma cell line HRA, highly invasive cells, with an expression vector harboring a cDNA encoding for human bik. This study was designed to investigate the effect of bik overexpression and changes in tumor cell phenotype and invasiveness in the stably transfected clones. Bik gene transfection of HRA gave the following results : (1) transfection of HRA with the bik cDNA resulted in five variants stably expressing functional bik ; (2) bik^+ clones exhibited a significantly reduced uPA mRNA expression as compared with the parental cells ; (3) bikunin negatively regulates the ERK1/2 activity ; (4) secretion-blocking treatments of bik^+ clones abrogated bik-mediated suppression of ERK1/2 activation and uPA expression ; (5) the regulation of invasion seen in the HRA cells is mainly mediated by the uPA-plasmin-MMP-2 system ; (6) transfection of HRA with the bik gene significantly reduced invasion, but not proliferation, adhesion, or migrate relative to the parental cells ; and (7) animals with bik^+ clones induced reduced peritoneal dissemination and long term survival. We conclude that transfection of HRA cells with the bik cDNA constitutively suppresses ERK1/2 activation which results in inhibition of uPA expression and subsequently reduces dissemination of bik^+ clones.
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