| Project/Area Number |
23590471
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Nara Medical University |
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Principal Investigator |
SHIMADA Keiji 奈良県立医科大学, 医学部, 講師 (90336850)
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| Co-Investigator(Renkei-kenkyūsha) |
TSUJIKAWA Kazutake 大阪大学, 薬学研究科, 教授 (10207376)
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| Project Period (FY) |
2011 – 2013
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | urothelial carcinoma / ALKBH3 / ROS / Tweak / Fn14 / VEGF / reactive oxygen species / 膀胱癌 / 活性酸素種 / NADPH oxidase / Reactive oxygen species / Urothelial carcinoma |
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| Research Abstract |
The role and function of ALKBH3 in human urothelial carcinoma development were examined. ALKBH3 knockdown induced cell cycle arrest at the G1 phase through downregulation of NOX-2-mediated generation of ROS. ALKBH3 knockdown reduced VEGF expression by reducing expression of Tweak and its receptor, Fn14. Silencing of ALKBH3 or Tweak significantly suppressed invasion and angiogenesis of urothelial carcinoma in vivo . Interestingly, not only urothelial carcinoma cells but also vascular endothelial cells within cancer foci expressed Fn14, which was strongly reduced by ALKBH3 and Tweak knockdown in vivo, suggesting that ALKBH3-dependent expression of Tweak stabilizes Fn14. Immunohistochemical examination showed high expression of ALKBH3, Tweak, and Fn14 in urothelial carcinoma, especially in high-grade, invasive carcinomas; moreover, Fn14-positive vessel counts within cancer foci were increased in invasive phenotypes. ALKBH3 contributes to development of urothelial carcinomas.
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