| Project/Area Number |
16390355
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KITAYAMA Joji The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (20251308)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAWA Hirokazu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 教授 (80228064)
TSURITA Giichiro The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助教 (80345206)
TAKEI Yoshiki The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助教 (10372369)
YATOMI Yutaka The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60200523)
KAISAKI Shoichi The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助教 (70291325)
石神 浩徳 東京大学, 医学部附属病院, 助手 (80372382)
須並 英二 東京大学, 医学部附属病院, 助手 (70345205)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2005: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2004: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | LPA / transactivation / Autotaxin / LysoPLD / colon cancer / mast cell / S1P / SIP / 大腸癌 / EGFR / C-Met / 胃癌 / COX-2 / VEGF / 浸潤 / 乳癌 |
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| Research Abstract |
1. Immunoprecipitation analysis revealed that Lysophosphatidic acid (LPA) induced a significant level of tyrosine phosphorylation of EGFR in DLD1 cells. The LPA-induced phosphorylation of EGFR was almost completely abrogated by either AG1478 or GM6001. LPA induced significant migration and IL-8 secretion in DLD1, both of which were singnificantly inhibited by AG1478 or GM6001. However, the inhibitory effects were only partial These results clearly indicate that LPA acts upstream of EGFR and compensates the EGF signal and antagonism of the EGF signal can not completely block tumor progression in colon cancer cells.
2. Autotaxin (ATX) is molecularly identical to lysophospholipase D (lysoPLD), which is the main enzyme in the production of LPA. We evaluated ATX/lysoPLD expression by immunohistochemical staining using a rat anti-ATX mAb in the human gastrointestinal tract, and found that submucosal mast cells (MC) highly expressed this enzyme. This was confirmed by immunofluorescent double staining using mAbs to tryptase and chymase. Isolated MC from human gastric tissue by an immunomagnetic method using CD117-microbeads showed positive staining for intracellular ATX/lysoPLD on flowcytometry. This was confirmed by western blotting of the isolated cells. Our data suggest that submucosal MC play important roles in various aspects of pathophysiology in the gastrointestinal tract by locally providing bioactive LPA through the production of ATX/lysoPLD.
3. Sphingosine-1-phosphate inhibit the adhesion of monocytic cell, U937, which was significantly inhibited by a specific inhibitor for S1P1 and S1P3, and functional mAbs to integrin alpha5beta1 and alphaVbeta3. This suggests that S1P support endothelaia integrity through these molecules.
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