Role of cytokine-inducible transcription factors in renal cell carcinoma

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591715
• 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): MARUMO Ken Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (80138130) ; MURAI Masaru Keio University, School of Medicine, Professor, 医学部, 教授 (90101956)
• Project Period (FY): 2003 – 2004
• Keywords: Renal cell carcinoma / cytokine / apoptosis / NF-κB / C / EBP / AP-2 / MAP kinase / Akt

Research Abstract

Renal cell carcinoma(RCC) is occasionally associated with paraneoplastic syndromes such as inflammatory reactions and leukocytosis. Cytokines produced by cancer cells are considered to accelerate cell growth in an autocrine or paracrine manner as well as induce cahexic reactions to the host. Furtheremore, Cytokine-dependent signal transduction has been implicated to play a role in maintaining cancer cell survival. Therefore, blocking the signal pathways may have a therapeutic potential for RCC. Transcription factors not only induce de novo cytokine expression, but their activities are also induced by cytokines and therefore may play a substantial role in cytokine-mediated autocrine growth in RCC. Increased activation of NF-κB, STAT3 and C/EBP-β were associated with a high tumor stage and grade. PI3K-Akt pathway has been implicated to regulate key effector molecules involved in controlling the balance of cell survival and apoptosis. Akt activation determined by immunohistochemistry associated with high tumor grade and metastatic disease. Immunoblotting studies revealed decreased PTEN expression is necessary but not sufficient for Akt activation. Akt inhibitor induced apoptosis in some RCC cell lines. MAP kinases include ERKs, JNK, and p38. ERKs are constitutively activated, but JNK and p38 are inactivated in a steady state of RCC. ERKs inactivation did not induce apoptosis, therfore, ERKs do not seem to relate to cell survival. In contrast, inductive JNK or p38 activation induced apoptosis in some RCC cell lines. Our investigation of signal transduction pathways shed some light on a potential novel treatment for RCC. These signal trasduction molecules mentioned above are candidates for molecular targeting therapy for RCC.

Research Products

• [Journal Article] Differential expression of activator protein-2 isoforms in renal cell carcinoma. (2004)
  • Author(s): Oya, M., Mikami, S., Mizuno, R., Miyajima, A., Horiguchi, Y., Nakashima, J., Marumo, K., Mukai, M., Murai, M.
  • Journal Title: Urology 64 Pages: 162-167
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells. (2004)
  • Author(s): Mizuno, R., Oya, M., Shiomi, T., Marumo, K., Okada, Y., Murai, M.
  • Journal Title: Journal of Urology 172 Pages: 723-727
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. (2004)
  • Author(s): Ishizawa, J., Yoshida S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., Murai, M.
  • Journal Title: International Journal of Oncology 25 Pages: 697-702
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma. (2003)
  • Author(s): Oya, M., Takayanagi, A., Horiguchi, A., Mizuno, R., Ohtsubo, M., Marumo, K., Shimizu, N., Murai, M.
  • Journal Title: Carcinogenesis 24 Pages: 377-384
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased activation of CCAAT/enhancer binding protein-β correlates with the invasiveness of renal cell carcinoma. (2003)
  • Author(s): Oya, M., Horiguchi, A., Mizuno, M., Marumo, K., Murai, M.
  • Journal Title: Clinical Cancer Research 9 Pages: 1021-1027
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Elevated AKT activation and its impact on clinicopathological features of renal cell carcinoma. (2003)
  • Author(s): Horiguchi, A., Oya, M., Shimada, T., Uchida, A., Marumo, K., Murai, M
  • Journal Title: Journal of Urology 169 Pages: 710-713
  • Description: 「研究成果報告書概要(和文)」より