Hypoxia responsiveness in renal cell carcinoma

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17591701
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: KEIO 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
• Keywords: hypoxia / renal cell carcinoma / hypoxia inducible factor / vascular endothelial growth factor / VEGF

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.

Research Products

• [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
• [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
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
• [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
• [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
• [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
• [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
• [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
• [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