Role of ornithine decarboxylase (ODC) as a oncogene in colorectal tumorigenesis

• Project/Area Number: 08671368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Okayama University
• Principal Investigator: TANAKA Noriaki Okayama University Medical School, Professor, 医学部, 教授 (10127566)
• Co-Investigator(Kenkyū-buntansha): MATSUBARA Nagahide Okayama University Medical School Hospital, Senior Resident, 医学部・附属病院, 医員 ; SHIMIZU Kenji Okayama University Medical School, Professor, 医学部, 教授 (10037286)
• Project Period (FY): 1996 – 1997
• Project Status: Completed (Fiscal Year 1997)
• Budget Amount: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 1997: ¥700,000 (Direct Cost: ¥700,000)
• Keywords: Colon cancer / ODC / genetic instability / E2F-4 / MSH3 / Colon cancer / qenetic instability / 大腸癌 / 点突然変異 / microsatellite instability / DNA修復異常

Research Abstract

Omithine decarboxylase, a critical regulatory enzyme for polyamine byosynthesis, is highly regulated in human colorectal cancer. Defects in mispatch repair function can lead to the microsateillite instability (MI) phenotype in certain human cancers. During our analysis of polyamine metabolism in colorectal cancinomas and its relationship to clinical parameters, we were struck by the similarity between published data of clorectalcancerpatients with MI phenotype and those patients in our series with high level of tumor ODC activity (especially a particular isoform of ODC which can be activated by GTP) : both sets of patients tend to have right sided tumors and good prognosis. We therefore examined the genetic alterations, such as mutations or the structural alterations, accounts for the tumor ODC.No mutations or structual alterations were detected in ODC genes from any of the colorectal tumor as well as normal tissue examined. These results suggest that mutation in coding sequence of ODC or structual alteration of the gene that might affect the charactristics of alterd ODC function may not be involved in human colorectal cancers.
In the course of our study of ODC and MI pohenotype, we have identified E2F-4, important transcription fuctor in cell-cycle control, having frequent tumor-specific mutations at the trinucleotide coding microsatellite (CAG repeats) in a subset of human sporadic CRC with MI phenotype. We also found a relatively high rate of mutation within E2F-4 in gastric cancer and ulcerative colitis related tumor with MI.Additional investigations revealed that somatic mutation in E2F-4 gene are closely associtated with defects in the hMSH3 gene and are possibly selectedduring the progression of colorectal MI tumors.

Research Products

• [Publications] Ikeda, M: "Close correlation between mutations of E2F-4 and hMSH3 genes in colorectal cancers with microsatellite instability" Cancer Res.58. 594-598 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Souza, R.F.: "Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors." Cancer Res.57. 2350-2353 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Matsubara, N.: "E2F-4 trinucleotide repeats is a target of microsatellite instability in human colorectal cancer but not in gastric cancer." Annu. Meet. Am. Assoc. Cancer Res.38. A2401 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Souza, R.F.: "Mutation in a coding region of E2F-4 in genetically unstable gastric tumors." Proc. Annu. Meet. Am. Assoc. Cancer Res.38. A2400 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Souza, R.F.: "Mutation of a coding region microsatellite within E2F-4 in genetically unstable gastrointestinal tumors." Gastrointestinal Oncology AGA Research Forum Digestive Disease Week. A1629 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yoshitaka, T.: "Mutation of E2F-4 trinucleotide repeats in colorectal cancer with microsatellite instability." Biochem. Biophys. Res. Commun.227. 553-557 (1996)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ikeda, M., Orimo, H., Moriyama, H., Nakajima, E., Matsubara, N., Mibu, R., Tanaka, N., Shimada, T., Kimura, A., and Shimizu, K: "Close correlation between mutations of E2F-4 and hMSH3 genes in colorectal cancers with microsatellite instability." Cancer Res.58. 594-598 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Souza, R.F., Yin, J., Smolinski, K.N., Zou, T-T., Wang, S., Shi, Y-Q., Rhyu, M-G., Cottrell, J., Abraham, J.M., Biden, K., Simms, L., Leggett, B., Bova, G.S., Frank, T., Powell, S.M., Sugimura, H., Young, J., Harpaz, N., Shimizu, K., Matsubara, N., Meltzer, S.J.: "Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors." Cancer Res.57. 2350-2353 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Matsubara, N., Yoshitaka, T., Ikeda, M., Takashima, H., Tanaka, N., and Shimizu, K.: "E2F-4 trinucleotide repeats is a target of microsatellite instability in human colorectal cancer but not in gastric cancer. (Meeting abstract)." Proc.Annu.Meet.Am.Assoc.Cancer Res.38. A2401 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Souza, R.F., Yin, J., Smolinski, K.N., Wang, S., Zou, T-T., Abraham, J.M., Powell, S.M., Sugimura, H., Matsubara, N., and Meltzer, S.J: "Mutation in a coding region of E2F-4 in genetically unstable gastic tumors." (Meeting abstract).Proc.Annu.Meet.Am.Assoc.Cancer Res.38. A2400 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] RF Souza, J Yin, KN Smolinski, S Wang, T-T Zou, JM Abraham, K Biden, L Simms, B Leggett, K Shimizu, SM Powell, H Sugimura, N Harpaz, J Young, N Matsubara and SJ Meltzer: "Mutation of a coding region microsatellite within E2F-4 in genetically unstable gastrointestinal tumors." (Meeting abstract) Gastrointestinal Oncology AGA Research Forum.Digestive Disease Week.A1629 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yoshitaka, T., Matsubara, N., Ikeda, M., Tanino, M., Hanafusa, H., Tanaka, N., and Shimizu, K.: "Mutation of E2F-4 trinucleotide repeats in colorectal cancer with microsatellite instability." Biochem.Biophys.Res.Commun.227. 553-557 (1996)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ikeda M, Orimo H, Morivama H, et al.: "Close correlation between mutations of E2F-4 and hMSH3 henes in colorectal cancers with microsatellite instability" Cancer Res.58(in press). (1998)
• [Publications] Souza RF, Yin J, Smolinski KN,et al.: "Frequent mutation of the E2F-4 cell cycle gene in primary human qastrointestinal tumors." Cancer Res.57. 2350-2353 (1997)
• [Publications] Yoshitaka T, Matsubara N, Ikeda M,et al.: "Mutation of E2F-4 trinucleotide repeats in colorectal cancer with microsatellite instability" Biochem.Biophys.Res.Commun.227. 553-557 (1997)
• [Publications] Matsubara N, Hietala OA, Gilmore SK,et al.: "Association between high levels of ornithine decarboxylase activity and favorable prognosis in human colorectal carcinoma." Clinical Cancer Research. 1. 665-671 (1995)