2002 Fiscal Year Final Research Report Summary
Molecular diagnosis and therapy based on mechanisms of the regulation of hypoxia-inducible
| Project/Area Number |
13672099
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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 |
Surgical dentistry
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
YOSHIGA Koji Division of Frontier Medical Science, Programs for Biomedical Research, Hiroshima University Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (70112216)
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| Co-Investigator(Kenkyū-buntansha) |
TANIMOTO Keiji Department of Translational Cancer Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Research Associate, 原爆放射線医科学研究所, 助手 (90335688)
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| Project Period (FY) |
2001 – 2002
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| Keywords | head and neck cancer / hypoxia / angiogenesis / hypoxia-inducible factor / transcription factor / genetic polymorphism / molecular epidemiology |
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| Research Abstract |
Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of cellular response to hypoxia and has been suggested as playing an important role in tumor progression and metastasis through activation of various genes that are linked to regulation of angiogenesis, erythropoiesis, energy metabolism, and so on. HIF-1α protein levels are regulated by the conditional interaction of HIF-1α with the von Hippel-Lindau tumor suppressor protein (pVHL), which functions as an E3 ubiquitin ligase predominantly targeting the minimal N-terminal transactivation domain (N-TAD) of HIF-1α. Very recently, two polymorphisms found in human HIF-1α gene were shown to cause amino-acid substitutions within or near the N-TAD, although the functional significance of these polymorphisms was not studied at the time, and no difference in genotype distribution was found between renal cell carcinoma patients and controls. We assessed the difference in transcription activity of the HIF-1α polymorphic variants (P582S and A588T), along with molecular epidemiological study among head and neck squamous cell carcinoma (HNSCC) patients. Both HIF-1α variants revealed significantly higher transcription activity than WT, under normoxic and hypoxic conditions. Furthermore, tumors from HNSCC patients with heterozygous alleles having P582S or A588T had significantly increased numbers of microvessels compared with those with homozygous. In addition, all patients with tumors of T1 (below 2 cm diameter) were WT, while 14 of 47 patients with tumors of 【greater than or equal】T2 were heterozygous. The elevated transactivation capacity of variant forms of HIF-1α implies a role of HIF-1α polymorphisms in generating individually-different tumor progression (submitted).
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Research Products
(14 results)
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[Publications] Hirao, K., Sugita, T., Kubo, T., Igarashi, K., Tanimoto, K., Murakami,T., Yasunaga, Y., and Ochi, M.: "Targeted gene delivery to human osteosarcoma cells with magnetic liposomes under a magnetic field"International Journal of Oncology. in press. (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Miyazaki, K., Kawamoto, T., Tanimoto, K., Nishiyama, M., Honda, H., and Kato, Y.: "Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes"Journal of Biological Chemistry. 277(49). 47014-47021 (2002)
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[Publications] Okamoto, R., Takano, H., Okamura, T., Park, J.S., Tanimoto, K., Sekikawa, T., Yamamoto, W., Sparreboom, A., Verweij, J., and Nishiyama, M.: "O^6-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives"Japanese Journal of Cancer Research. 93. 93-102 (2002)
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[Publications] Park, J.S., Yamamoto, W., Sekikawa, T., Matsukawa, M., Okamoto, R., Sasaki, M., Ukon, K., Tanimoto, K., Kumazaki, T., and Nishiyama, M.: "Cellular sensitivity determinants to docetaxel in human gastrointestinal cancers"International Journal of Oncology. 20. 333-338 (2002)
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[Publications] Okamoto, R., Takano, H., Sekikawa, T., Tanaka, T., Toyoda, M., Ukon, K., Tanimoto, K., Kumazaki, T., and Nishiyama, M.: "Unique action determinants of double acting topoisomerase inhibitor"International Journal of Oncology. TAS-103, 19. 921-927 (2001)
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「研究成果報告書概要(欧文)」より
