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Molecular diagnosis and therapy based on mechanisms of the regulation of hypoxia-inducible

Research Project

Project/Area Number 13672099
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Surgical dentistry
Research InstitutionHIROSHIMA UNIVERSITY

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)

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)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordshead and neck cancer / hypoxia / angiogenesis / hypoxia-inducible factor / transcription factor / genetic polymorphism / molecular epidemiology / hyupoxia / Hypoxia / HIF-1 / oral squamous cell carcinoma
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).

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Teresa Pereira: "Identification of Residues Critical for Regulation of Protein Stability and the Transactivation Function of the Hypoxia-Inducible Factor-1α by the von Hippel-Lindau Tumor Suppresor Gene Product"Journal of Biological Chemistry. 278. 6816-6823 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazuko Miyazaki: "Identification of Functional Hypoxia Response Elements in Promoter Region of the DEC1 and DEC2 Gene"Journal of Biological Chemistry. 277. 47014-47021 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 谷本 圭司: "低酸素と遺伝子不安定性"癌治療と宿主. (印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masao Sasaki: "Bcl-2 in cancer and normal tissue cells as a prediction marker of response to 5-fluorouracil"International Journal of Oncology. 22. 181-186 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ryo Okamoto: "O^6-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives"Japanese Journal of Cancer Research. 19. 93-102 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Keiji Tanimoto: "Human Genetics"Research Signpot, Kerala, India (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanimoto, K., and Nishiyam, M.: "Genome instability in hypoxic cancer cells"Frontiers in Cancer Treatment(in Japanese). 15 (3), In press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Pereira, T., Zheng, X., Raus, J. L., Tanimoto, K., and Poellinger, L.: "Identification of residues critical for regulation of protein stability and the transactivation function of hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor gene product"Journal of Biological Chemistry. 278(9). 6816-6823 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sasaki, M., Kumazaki, T., Tanimoto, K., and Nishiyama, M.: "Bcl-2 in cancer and normal tissue cells as a prediction marker of response to 5-fluorouracil"International Journal of Oncology. 22. 181-186 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Teresa Pereira: "Identification of Residues Critical for Regulation of Protein Stability and the Transactivation Function of the Hypoxia-Inducible Factor-1α by the von Hippel-Lindau Tumor Suppresor Gene Product"Journal of Biological Chemistry. 278. 6816-6823 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kazuko Miyazaki: "Identification of Functional Hypoxia Response Elements in Promoter Region of the DEC1 and DEC2 Gene"Journal of Biological Chemistry. 277. 47014-47021 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Keiji Tanimoto: "Human Genetics"Research Signpot, Kerala, India (editors, K. Hiyama and E. Hiyama) (in press).

    • Related Report
      2002 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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