| Project/Area Number |
23701094
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Clinical oncology
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
TANAKA Hiroki 旭川医科大学, 医学部, 特任講師 (70596155)
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | HIF-1alpha / 鉄 / HIF-1α / HIF-1 alpha |
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| Research Abstract |
Targeting HIF-1a has been of therapeutic interest. In normoxic conditions, HIF-1a is hydroxylated by prolylhydroxylases (PHDs), which require iron for its activity. The tumor suppressor protein VHL binds to the hydroxylated HIF-1a, which is then degraded by proteasomes. We focused on the degradation machinery of HIF-1a mediated by PHDs. In this study, we aimed to inhibit the expression of HIF-1a protein and growth of hepatocellular carcinoma (HCC) using the iron-facilitating activity of LS5-81. In the human HCC cell lines, a combination of LS5-81 and iron inhibited HIF-1a protein expression. A mutated HIF-1a protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS5-81 and iron. Furthermore, LS5-81 inhibited tumor growth of mouse HCC models. These results indicate that LS5-81 inhibits HIF-1a expression through prolyl-hydroxylation of HIF-1a and might have a therapeutic effect in the treatment of HCC.
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