Gross I, Duluc I, Benameur T, Calon A, Martin E, Brabletz T, Kedinger M, Domon-Dell C, Freund J-N
INSERM, U682, Strasbourg, France.
Oncogene. 2008 Jan 3;27(1):107-15. doi: 10.1038/sj.onc.1210601. Epub 2007 Jun 25.
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.
结直肠癌的严重性主要归因于肿瘤细胞从肿瘤块中迁移出来侵袭基质并作为转移灶扩散的能力。在伤口愈合过程中也会出现迁移表型的获得。在此，我们表明，体外伤口修复过程中迁移的细胞具有一些侵袭性结肠肿瘤细胞所特有的特征。特别是，肠道特异性转录因子Cdx2在侵袭性癌细胞中下调，是维持肠道特性的关键基因，在体外伤口愈合过程中其表达降低。参与上皮-间质转化的转录因子，如Snail和Slug，在伤口愈合过程中上调，并且能够抑制Cdx2转录。在体外，在人结肠癌细胞系中强制表达Cdx2会延迟伤口修复并减少迁移，而通过RNA干扰抑制Cdx2表达则会增强迁移。在体内，强制表达Cdx2可对抗肿瘤细胞在三个不同部位异种移植的裸鼠中的扩散。这些数据证明Cdx2可拮抗肿瘤细胞的扩散过程，并且表明这个同源盒基因可能代表针对结肠癌转移扩散的一个新的治疗靶点。
