| Project/Area Number |
15390222
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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 |
Gastroenterology
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
KOBAYASHI Takahiko Hokkaido Univ., Hokkaido University Hospital, Lec., 病院, 講師 (80333607)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Masanobu Hokkaido Univ., Genetic Medicine, Asso.Prof., 遺伝子病制御病研究所, 助教授 (80241321)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
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| Keywords | Pancreatic Cancer / HIF-1 / Hypoxia / 低酸素適応 / 血管新生 / ドミナント・ネガティブ |
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| Research Abstract |
In the tumor cells exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1)-mediated adaptation responses such as angiogenesis and anaerobic metabolism are induced for their survival. We have recently reported that the constitutive expression of HIF-1 renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and glucose deprivation. First, we established dominant-negative HIF-1 (DN HIF-1) transfectants and examined their susceptibility to apoptosis and growth inhibition induced by hypoxia and glucose deprivation in vitro and their tumorigenicity in SCID mice. We then examined the expressions of aldolase A and Glut-1 in vitro and Glut-1 expression and glucose uptake in the tumor. DN HIF-1 rendered the pancreatic cancer cells sensitive to apoptosis and growth inhibition induced by hypoxia and glucose deprivation. Also it abrogated the enhanced expression of Glut-1 and aldolase A mRNAs under hypoxia and reduced the expression of Glut-1 and the glucose uptake in the tumor tis
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sues and consequently in vivo tumorigenicity.
Next, we sought to identify the metastasis-associated genes differentially expressed in tumor cells under hypoxic. We found that hypoxia enhanced the expression of autocrine motility factor (AMF) mRNA in pancreatic cancer cells and also enhanced their random motility. On the other hand, DN HIF-1 suppressed the expression of AMF mRNA and the random motility. These results suggest that hypoxia promotes the metastatic potential of cancer cells through the enhanced AMF expression and that the disruption of the HIF-1 pathway may be an effective treatment for metastasis.
We also examined the effects of adrenomedullin antagonist on the growth of pancreatic cancer cells since hypoxia induced the expression of adrenomedullin. The growth of pancreatic cancer cell lines was significantly reduced by the antagonist in vitro and in vivo. These results suggest that adrenomedullin antagonist might be a useful tool for treating pancreatic cancers.
Taken together, we suggest that the disruption of the HIF-1 pathway by DN HIF-1 might be effective in the treatment of pancreatic cancers. Less
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