Bui L-C, Tomkiewicz C, Chevallier A, Pierre S, Bats A-S, Mota S, Raingeaud J, Pierre J, Diry M, Transy C, Garlatti M, Barouki R, Coumoul X
INSERM UMR-S 747, Paris, France.
Oncogene. 2009 Oct 15;28(41):3642-51. doi: 10.1038/onc.2009.224. Epub 2009 Aug 3.
Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.
芳烃受体（AhR），即二噁英受体，是一种转录因子，可响应环境污染物诱导适应性代谢途径。最近，发现AhR及其配体可改变其他途径。事实上，AhR配体引发的发育缺陷表明该受体可能靶向其他细胞功能，包括细胞迁移和可塑性。在此，我们表明二噁英介导的Ahr激活可诱导Nedd9/Hef1/Cas-L，这是一种最近被鉴定为转移标志物的Cas蛋白家族成员。Hef1基因的诱导由该基因启动子中存在的两个外源性反应元件介导。此外，使用RNA干扰，我们表明Nedd9/Hef1/Cas-L介导了与细胞可塑性相关的二噁英引发的变化，包括细胞粘附和形状的改变、细胞骨架重组以及细胞迁移增加。此外，我们表明二噁英和AhR对E-钙粘蛋白的抑制和Jun N-末端激酶的激活也依赖于Nedd9/Hef1/Cas-L的表达。我们的研究首次揭示了污染物暴露与转移标志物诱导表达之间的联系，并表明细胞迁移和可塑性标志物受AhR及其有毒配体的调节。
