The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells
The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells
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DOI：
10.1038/sj.onc.1210601
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发表时间：
2008-01-03
期刊：
影响因子：
8
通讯作者：
Freund, J-N
中科院分区：
文献类型：
--
作者：
Gross, I.;Duluc, I.;Freund, J-N
结直肠癌的严重性主要是由于肿瘤细胞迁移出肿瘤块以侵入基质并作为转移而扩散的能力。迁移表型的获得也发生在伤口愈合期间。在这里，我们表明，在体外伤口修复过程中，侵袭性结肠肿瘤细胞的几个特征是由迁移细胞共享的。特别地，在体外伤口愈合期间，在侵袭性癌细胞中下调的肠身份的关键基因--精氨酸特异性转录因子Cdx 2的表达降低。参与上皮-间充质转化的转录因子如Snail和Slug在伤口愈合期间上调，并且能够抑制Cdx 2转录。在体外，Cdx 2在人结肠癌细胞系中的强制表达延缓了伤口修复并减少了迁移，而通过RNA干扰抑制Cdx 2表达增强了迁移。在体内，Cdx 2的强制表达反对肿瘤细胞在三个不同部位异种移植的裸鼠中扩散。这些数据提供了Cdx 2拮抗肿瘤细胞扩散过程的证据，并且它们表明这种同源异型盒基因可能代表针对结肠癌转移扩散的新的治疗靶点。
The gravity of colorectal cancer is mainly due to the capacity of tumor cells to migrate out of the tumor mass to invade the stroma and disseminate as metastases. The acquisition of a migratory phenotype also occurs during wound healing. Here, we show that several features characterizing invasive colon tumor cells are shared by migrating cells during wound repair in vitro. In particular, the expression of the intestine-specific transcription factor Cdx2, a key gene for intestinal identity downregulated in invasive cancer cells, is reduced during wound healing in vitro. Transcription factors involved in epithelial-mesenchymal transition such as Snail and Slug are upregulated during wound healing and are able to repress Cdx2 transcription. In vitro, forced expression of Cdx2 in human colon cancer cell lines retarded wound repair and reduced migration, whereas inhibition of Cdx2 expression by RNA interference enhanced migration. In vivo, forced expression of Cdx2 opposed tumor cells spreading in nude mice xenografted at three different sites. These data provide evidence that Cdx2 antagonizes the process of tumor cell dissemination, and they suggest that this homeobox gene might represent a new therapeutic target against metastatic spreading of colon cancer.