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

鸟氨酸脱羧酶（ODC）作为癌基因在结直肠肿瘤发生中的作用

• 批准号: 08671368
• 负责人: TANAKA Noriaki
• 金额: $ 0.45万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671368/
• 关键词: 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

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.

鸟氨酸脱羧酶是多胺合成的关键调节酶，在人结直肠癌中受到高度调节。错配修复功能的缺陷可导致某些人类癌症中的微卫星不稳定性（MI）表型。在我们分析结直肠癌中多胺代谢及其与临床参数的关系时，我们惊讶于具有MI表型的结直肠癌患者和我们系列中具有高水平肿瘤ODC活性（特别是可被GTP激活的ODC的特殊亚型）的患者的已发表数据之间的相似性：两组患者都倾向于右侧肿瘤和良好的预后。因此，我们检查了肿瘤ODC的遗传改变，如突变或结构改变，在任何结直肠肿瘤和正常组织中均未检测到ODC基因的突变或结构改变。这些结果表明，ODC编码序列的突变或基因结构的改变可能不影响ODC功能改变的特征，在我们对ODC和MI表型的研究过程中，我们鉴定了E2 F-4，它是细胞周期调控的重要转录因子，在具有MI表型的人类散发性CRC亚组中，三核苷酸编码微卫星（CAG重复序列）频繁发生肿瘤特异性突变。我们还发现E2 F-4基因在胃癌和溃疡性结肠炎相关肿瘤中有较高的突变率，进一步的研究表明，E2 F-4基因的体细胞突变与hMSH 3基因的缺陷密切相关，并可能在结直肠MI肿瘤的进展过程中被选择。

项目成果

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)

Yoshitaka T、Matsubara N、Ikeda M 等人：“结直肠癌中 E2F-4 三核苷酸重复序列的微卫星不稳定性突变”Biochem.Biophys.Res.Commun.227。

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)

Ikeda M、Orimo H、Morivama H 等人：“结直肠癌中 E2F-4 和 hMSH3 henes 突变与微卫星不稳定性之间的密切相关性”Cancer Res.58（出版中）。

Souza, R.F.: "Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors." Cancer Res.57. 2350-2353 (1997)

Souza, R.F.：“原发性人类胃肠道肿瘤中 E2F-4 细胞周期基因的频繁突变。”

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 gast

RF Souza、J Yin、KN Smolinski、S Wang、T-T Zou、JM Abraham、K拜登、L Simms、B Leggett、K Shimizu、SM Powell、H Sugimura、N Harpaz、J Young、N Matsubara 和 SJ Meltzer：“突变

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)

Souza, R.F.：“遗传不稳定胃肿瘤中 E2F-4 编码区的突变。”