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Hypoxia responsiveness in renal cell carcinoma

Research Project

Project/Area Number 17591701
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionKEIO UNIVERSITY

Principal Investigator

OYA Mototsugu  Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (00213885)

Co-Investigator(Kenkyū-buntansha) MURAI Masaru  Keio University, School of Medicine, Professor, 医学部, 教授 (90101956)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordshypoxia / renal cell carcinoma / hypoxia inducible factor / vascular endothelial growth factor / VEGF / HIF / VHL
Research Abstract

Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1α and HIF-2α. VHL gene was inactivated in 4 of 9 cell lines, due to frame shift mutation or hypermethylation. All four cell lines with VHL gene activation had either a truncated or defective HIF-1α expression. Transcriptional silencing, accompanying aberrant CpG island promotor region methylation or truncated mRNA expression was observed in 5 of 9 cell lines which resulted in the absence of wild type HIF-1α protein expression. The reduced potein expression was due to a low level of mRNA expression. Therefore, as a whole, protein expression was correlated with mRNA expression. In the cell lines devoid of HIF-1α expression, VEGF expression was maintained by HIF-2α expression. Indeed, 769P cell lacking both HIF-1α and HIF-2α had low VEGF expression. In these HIF-1α defective cell lines, the knockdown of the HIF-2α gene demonstrated that HIF-2α regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1α played a predominant role in VEGF secretion in the cells expressing both wild type HIF-1α and HIF-2α proteins. The transcriptional silencing or truncated mRNA expression of HIF-1α was a common phenomenon in human RCC cell lines. HIF-1α may therefore represent an important target molecule for RCC therapy, however, HIF-2α should be targeted in HIF-1α defective renal cancer cells.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (18 results)

All 2007 2006 2005

All Journal Article (18 results)

  • [Journal Article] Renal cancer cells lacking hypoxia inducible factor (HIF) 1-α expression maintain vascular endothelial growth factor expression through HIF 2-α.2007

    • Author(s)
      Shinojima, T., Oya, M., Takayanagi, A., Mizuno, R., Shimizu, N., Murai, M.
    • Journal Title

      Carcinogenesis 28

      Pages: 529-536

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Renal cancer cells lacking hypoxia inducible factor (HIF) 1-α expression maintain vascular endotheltal growth factor expression through HIF 22007

    • Author(s)
      Shinojima, T., Oya, M., Takayanagi, A., Mizuno, R., Shimizu, N., Murai, M.
    • Journal Title

      Carcinogenesis 28

      Pages: 529-536

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Interleukin 6 is associated with cahexia in patients with prostate cancer.2007

    • Author(s)
      Kuroda, K., Nakashima, J., Kanao, K., Kikuchi, E., Miyajima, A., Horiguchi, Y., Nakagawa K., Oya, M., Ohigashi, T., Mrai, M.
    • Journal Title

      Urology 69

      Pages: 113-117

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Survivin associates with cell proliferation in renal cancer cells : Regulation of survivin expression by insulin-like growth factor-1, interferon-gamma and a novel NF-kappaB inhibitor.2006

    • Author(s)
      Sato A., Oya, M., Ito K., Mizuno, R., Horiguchi, Y., Ohigashi, T., Umezawa K., Hayakawa M., Murai, M.
    • Journal Title

      Int. J. Oncol 28

      Pages: 841-846

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Expression of Ets-1 in human clear cell renal cell carcinomas : implications for angiogenesis.2006

    • Author(s)
      Mikami, S., Oya, M., Mizuno, R., Murai, M., Mukai, M., Okada, Y.
    • Journal Title

      Cancer Sci. 97

      Pages: 875-882

    • NAID

      10018767423

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Survivin associates with cell proliferation in renal cancer cells : Regulation of survivin expression by insulin-like growth factor-1, interferon-gamma and a novel NF-kappaB inhibitor.2006

    • Author(s)
      Sato A., Oya, M., Ito K., Mizuno, R., Horiguchi, Y., Ohigashi, T., Umezawa K., Hayakawa M., Murai, M.
    • Journal Title

      Int.J.Oncol. 28

      Pages: 841-846

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Maximum tumor diameter is a smple and valuable index associated with the local extent of disease in clinically localized prostate cancer.2006

    • Author(s)
      Mizuno, R., Nakashima, J., Mukai, M., Ookita, H., Nakagawa, K., Oya, M., Ohigashi, T., Marumo, K., Murai, M.
    • Journal Title

      Int. J. Urol 13

      Pages: 951-955

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of Ets-1 in human clear cell renal cell carcinomas : implications for angiogenesis.2006

    • Author(s)
      Mikami, S., Oya, M., Mizuno, R., Murai, M., Mukai, M., Okada, Y.
    • Journal Title

      Cancer Sci 97

      Pages: 875-882

    • NAID

      10018767423

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Akt activation in renal cell carcinoma : contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.2005

    • Author(s)
      Hara, S., Oya, M., Mizuno, R., Horiguchi, A., Marumo, K, Murai, M.
    • Journal Title

      Ann. Oncol. 16

      Pages: 928-933

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] C-jun activation in acquired cystic kidney disease and renal cell carcinoma.2005

    • Author(s)
      Oya, M., Mikami, S., Mizuno, R., Marumo, K., Mukai, M., Murai, M.
    • Journal Title

      J. Urol. 174

      Pages: 726-730

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells.2005

    • Author(s)
      Mizuno, R., Oya, M., Hara, S., Matsumoto, M., Horiguchi, A., Ohigashi, T., Marumo, K., Murai, M.
    • Journal Title

      Oncol. Rep 14

      Pages: 639-644

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Akt activation in renal cell carcinoma : contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.2005

    • Author(s)
      Hara, S., Oya, M., Mizuno, R., Horiguchi, A., Marumo, K., Murai, M.
    • Journal Title

      Ann.Oncol. 16

      Pages: 928-933

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] C-jun activation in acquired cystic kidney disease and renal cell carcinoma.2005

    • Author(s)
      Oya, M., Mikami, S., Mizuno, R., Marumo, K., Mukai, M., Murai, M.
    • Journal Title

      J.Urol. 174

      Pages: 726-730

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells.2005

    • Author(s)
      Mizuno, R., Oya, M., Hara, S, Matsumoto, M, Horiguchi, A, Ohigashi, T, Marumo, K, Murai, M.
    • Journal Title

      Oncol.Rep. 14

      Pages: 639-644

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Akt activation in renal cell carcinoma : contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.2005

    • Author(s)
      Hara, S., Oya, M., Mizuno, R., Horiguchi, A., Marumo, K., Murai, M.
    • Journal Title

      Ann Oncol 16

      Pages: 928-933

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alfa preparations.2005

    • Author(s)
      Oya, M., Asakura, H., Mizuno, R., Marumo, K., Murai, M.
    • Journal Title

      Biomed Res 26

      Pages: 135-137

    • Related Report
      2005 Annual Research Report
  • [Journal Article] C-jun activation in acquired cystic kidney disease and renal cell carcinoma.2005

    • Author(s)
      Oya, M., Mikami, S., Mizuno, R., Marumo, K., Mukai, M., Murai, M.
    • Journal Title

      J Urol 174

      Pages: 726-730

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells.2005

    • Author(s)
      Mizuno, R., Oya, M., Hara, S., Matsumoto, M., Horiguchi, A., Ohigashi, T., Marumo, K., Murai, M.
    • Journal Title

      Oncol Rep 14

      Pages: 639-644

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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