Identification of candidate cooperative genes of the Apc mutation in transformation of the colon epithelial cell by retroviral insertional mutagenesis
Identification of candidate cooperative genes of the Apc mutation in transformation of the colon epithelial cell by retroviral insertional mutagenesis
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DOI：
10.1111/j.1349-7006.2008.00757.x
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发表时间：
2008-05-01
期刊：
影响因子：
5.7
通讯作者：
Nakamura, Takuro
中科院分区：
文献类型：
--
作者：
Tanaka, Miwa;Jin, Guang;Nakamura, Takuro
APC基因突变是结肠癌发生的重要早期遗传学事件。然而，需要什么样的协同基因才能完全致癌，这一点仍有待阐明。为了确定APC(Min)突变的协同基因，作者用Min小鼠来源的IMCE结肠上皮细胞进行了逆转录病毒插入突变(RIM)。逆转录病毒感染只能在IMCE细胞中诱导不依赖锚定的转化集落，而在APC正常的幼年小鼠结肠(YAMC)细胞中未发现转化。共检测到157个逆转录病毒整合位点，其中Dnah3、AHNAK、Stk17b和Rbm9是4个常见的整合位点。由于病毒整合，Dnah3和AHNAK基因上调，Dnah3基因截短。此外，Dnah3过表达的IMCE细胞显示微管功能受损。这些数据提示细胞骨架功能在APC相关肿瘤发展中的重要性，以及RIM在非造血组织中的应用，为结肠癌的早期发生提供了新的见解。
The mutation of Apc is an important early genetic event in colon carcinogenesis. However, it remains to be clarified what kinds of cooperative genes are required for complete carcinogenesis. To identify cooperative genes for the Apc(Min) mutation the authors carried out retroviral insertional mutagenesis (RIM) using Min mouse-derived IMCE colon epithelial cells. Anchorage-independent transformed colonies were induced by retroviral infection only in IMCE cells, while no transformation was found in young adult mouse colon (YAMC) cells that are normal for Apc. One hundred and fifty-seven retroviral integration sites (RIS) were identified in 101 independent transformants, and four common integration sites (CIS), Dnah3, Ahnak, Stk17b and Rbm9, were observed. Upregulation of Dnah3 and Ahnak, and truncation of Dnah3 due to the viral integration, was revealed. In addition, Dnah3-overexpressing IMCE cells showed impairment of microtubule function. These data suggest the importance of cytoskeletal function in Apc-related tumor development and the usefulness of RIM in non-hematopoietic tissues, providing new insight into the early stage of colon carcinogenesis.