Tanaka Miwa, Jin Guang, Yamazaki Yukari, Takahara Tomoko, Takuwa Miki, Nakamura Takuro
Department of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Cancer Sci. 2008 May;99(5):979-85. doi: 10.1111/j.1349-7006.2008.00757.x. Epub 2008 Feb 24.
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.
Apc基因的突变是结肠癌发生过程中一个重要的早期遗传事件。然而，完整的致癌过程还需要哪些协同基因仍有待阐明。为了鉴定与Apc(Min)突变协同作用的基因，作者利用源自Min小鼠的IMCE结肠上皮细胞进行了逆转录病毒插入诱变（RIM）。仅在IMCE细胞中，逆转录病毒感染诱导了不依赖贴壁的转化菌落，而在Apc正常的成年小鼠结肠（YAMC）细胞中未发现转化现象。在101个独立的转化体中鉴定出157个逆转录病毒整合位点（RIS），并观察到4个常见整合位点（CIS），即Dnah3、Ahnak、Stk17b和Rbm9。结果显示Dnah3和Ahnak表达上调，且由于病毒整合导致Dnah3截短。此外，过表达Dnah3的IMCE细胞显示微管功能受损。这些数据表明细胞骨架功能在Apc相关肿瘤发生中的重要性以及RIM在非造血组织中的实用性，为结肠癌发生的早期阶段提供了新的见解。
