Regulation of Aquaporin 3 Expression by the AhR Pathway Is Critical to Cell Migration

The regulation of cell migration is a key factor for the dissemination of metastatic cells during tumor progression. Aquaporins are membrane channels which allow transmembrane fluxes of water and glycerol in cells in a variety of mammalian tissues. Here, we show that AQP3, which has been incriminated in cancer progression, is regulated by the AhR, or dioxin receptor. AhR is a transcription factor which is triggered in response to environmental pollutants and it has been shown to regulate several cellular processes including cell migration and plasticity. In vivo, upon exposure to the aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the expression of AQP3 is increased significantly in several murine tissues including the liver. In vitro, treatment of human HepG2 cells with TCDD also increased the expression of AQP3 mRNA and protein. These effects resulted from the activation of AhR as shown by RNA interference, chromatin immunoprecipitation and the use of several AhR ligands. Immunofluorescence and real-time analysis of cell migration (XCelligence) demonstrated that knockdown of AQP3 mRNA using small interfering RNA impairs the remodeling of cell shape and the triggering of cell migration that is induced by TCDD. Our work reveals, for the first time, a link between exposure to pollutant and the induction of an aquaporin which has been suspected to play a role during metastasis.