Genetic alterations and reduced expression of the DPC4 molucule in colorectal cancers and relationship to liver metastasis

结直肠癌中 DPC4 分子的遗传改变和表达减少及其与肝转移的关系

• 批准号: 11671220
• 负责人: GOI Takanori
• 金额: $ 2.11万
• 依托单位: Fukui Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671220/
• 关键词: DPC4; MADR2; colorectal cancer; liver metastasis

The isolated Smad genes constitute an evolutionarily conserved gene family. The smads proteins have been shown to be essential intracellular mediators of the growth inhibitory effects of TGF-β. These proteins are phosphorylated by the respective transmembrane serine threonine kinase receptor, and translocates to nucleus, where it acts as a regulator of transcription. To investigate the role of DPC4 gene and Madr2 genes in advanced colorectal cancers, we analyzed 29 colorecrtal specimens for alterations in DPC4 gene and Madr2 genes. An alterstion of the DPC4 gene sequence was identified in 6 (20.7%) of 29 colorectal cancers, and the distinct Madr2 gene mobility shifts were present in 3 (10.3%) cancers.We established a monoclonal antibody that specifically reacts with DPC4 products, using a fusion protein of DPC4 products for immunization. Immunoblots of samples from 64 paires of colorectal cancers and adjacent normal tissues revealed that all normal colorectal tissues significantly expressed the DPC4 protein, whereas colorectal cancer tissues showed poor expression. The ratio of DPC4 protein (cancer/normal) in colorectal cancer patients with liver metastasis expressed significantly low levels than those without. There were no significant differences between the ratio of DPC4 protein and the other clinicopathological findings.Our findings suggest that TGF-β-Smads pathway may be important determinants for tumorigenesis and liver metastasis in colorectal cancers

分离的Smad基因构成了一个进化保守的基因家族。smads蛋白已被证明是TGF-β生长抑制作用必不可少的细胞内介质。这些蛋白被各自的跨膜丝氨酸苏氨酸激酶受体磷酸化，并易位到细胞核，在那里它作为转录的调节剂。为了研究DPC4基因和Madr2基因在晚期结直肠癌中的作用，我们分析了29例结直肠标本中DPC4基因和Madr2基因的改变。29例结直肠癌中有6例（20.7%）存在DPC4基因序列的改变，3例（10.3%）存在明显的Madr2基因迁移。我们建立了一种与DPC4产物特异性反应的单克隆抗体，利用DPC4产物的融合蛋白进行免疫。64对结直肠癌及邻近正常组织的免疫印迹结果显示，所有正常结直肠癌组织均显著表达DPC4蛋白，而结直肠癌组织表达较差。DPC4蛋白在有肝转移的结直肠癌患者中的表达水平明显低于无肝转移的结直肠癌患者。DPC4蛋白比例与其他临床病理结果无显著性差异。我们的研究结果提示TGF-β-Smads通路可能是结直肠癌肿瘤发生和肝转移的重要决定因素