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，在人类结直肠癌中受到高度调节。错配修复功能的缺陷可能导致某些人类癌症中的微卫星不稳定性（MI）表型。在我们对结直肠癌中的多胺代谢及其与临床参数的关系进行分析的过程中，我们对已发表的具有 MI 表型的结直肠癌患者的数据与我们系列中具有高水平肿瘤 ODC 活性（尤其是 ODC 的特定亚型）的患者之间的相似性感到震惊可被 GTP 激活）：两组患者均倾向于右侧肿瘤，预后良好。因此，我们检查了导致肿瘤 ODC 的遗传改变，例如突变或结构改变。在任何结直肠肿瘤以及所检查的正常组织的 ODC 基因中均未检测到突变或结构改变。这些结果表明，ODC编码序列的突变或可能影响ODC功能改变特征的基因结构改变可能与人类结直肠癌无关。在我们对ODC和MI表型的研究过程中，我们鉴定了E2F -4，细胞周期控制中的重要转录子，在患有 MI 的人类散发性 CRC 子集中，三核苷酸编码微卫星（CAG 重复）频繁出现肿瘤特异性突变表型。我们还发现胃癌和溃疡性结肠炎相关肿瘤中的E2F-4突变率相对较高，并伴有MI。进一步的研究表明，E2F-4基因的体细胞突变与hMSH3基因的缺陷密切相关，并且可能是在疾病进展过程中选择的。结直肠 MI 肿瘤。