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Elucidation of the genesis mechanism of early lesions of colon cancer-Toward the elucidation of early lesions of de novo colorectal ceancer in humans

阐明结肠癌早期病变的发生机制——致力于阐明人类新发结直肠癌的早期病变

基本信息

批准号：
18590710
负责人：
OCHIAI Masako
金额：
$ 2.49万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590710/
关键词：
aberrant crypt foci early lesions of colon cancer de novo colorectal cancer

项目摘要

ACF-D(I) is a dysplastic lesion which belongs to classical ACF. ACF-D(II) is composed of crypts the as same as or smaller than normal crypts, detected mucin loss, high grade dysplastic lesions, and is hard to detect by classical staining methods but can be detected by a differential staining method (Ochiai et al., Cancer Lett, 220:67-74, 2005). Using a colon cancer model in rodents, I propose that the genesis mechanism of ACF-D(II) be made clear, and study whether ACF-D(II) may be an early lesion of de novo colorectal cancer and the character of that be elucidated. This was analyzed in the points below using colonic lesions of rats induced by azoxymethane.1. Gene-specific analysis of the genesis mechanism of ACF-D(II) using immunohistochemical analysis.In all five ACF-D(II) with mucin loss, Muc2 protein, which is major component of mucus in colon, was lost but dystopic expression of Muc5AC protein, which is a major component of mucus in the stomach, was not detected. In ACF-D(II), the expression of Cdx2 protein, which activated gene expression of Muc2 through Muc2 promoter, was almost the same as those in normal crypts and ACF-D(I).Runx3 is the target of the TGF-β superfamily and a putative tumor suppressor gene. Loss of Runx3 protein was not detected in five ACF-D(I), but detected in all four ACF-D(II). It was suggested that loss of Runx3 protein frequently occurred in ACF-D(II) but not ACF-D(I). Furthermore, it will be verified whether loss of Runx3 protein is specific in ACF-D(II) or not.2. Comprehensive analysis in genome of the genesis mechanism of ACF-D(II) using array-CGHIn three colon cancers, copy number aberration (CNA) with continuous loss of plural probes was not detected. So it was estimated that CNA may not be detected in ACF-D(II), pre-cancerous lesions in colon.

ACF-D(I)是一种发育不良病变，属于经典ACF。 ACF-D(II)由与正常隐窝相同或小于正常隐窝的隐窝组成，检测到粘蛋白丢失、高度发育不良病变，并且很难通过经典染色方法检测到，但可以通过差异染色方法检测到(Ochiai等，Cancer Lett，220:67-74, 2005)。笔者建议利用啮齿动物结肠癌模型，明确ACF-D(II)的发生机制，研究ACF-D(II)是否可能是新发结直肠癌的早期病变，并阐明其特征。使用氧化偶氮甲烷引起的大鼠结肠损伤对此进行了以下分析： 1．使用免疫组织化学分析对 ACF-D(II) 发生机制进行基因特异性分析。在所有 5 个粘蛋白缺失的 ACF-D(II) 中，结肠粘液主要成分 Muc2 蛋白缺失，但未检测到胃粘液主要成分 Muc5AC 蛋白的异位表达。在ACF-D(II)中，Cdx2蛋白的表达与正常隐窝和ACF-D(I)中的表达几乎相同，Cdx2蛋白通过Muc2启动子激活Muc2的基因表达。Runx3是TGF-β超家族的靶标，也是假定的抑癌基因。在 5 个 ACF-D(I) 中未检测到 Runx3 蛋白丢失，但在所有 4 个 ACF-D(II) 中均检测到。有人认为，Runx3 蛋白的丢失经常发生在 ACF-D(II) 中，而不是 ACF-D(I) 中。此外，还将验证Runx3蛋白的丢失是否在ACF-D(II)中具有特异性。2．使用array-CGH对ACF-D(II)的发生机制进行基因组综合分析在三种结肠癌中，未检测到伴随多个探针连续丢失的拷贝数畸变(CNA)。因此推测结肠癌前病变ACF-D(II)中可能检测不到CNA。