Systematic identification of molecular mechanisms for aryl hydrocarbon receptor mediated neuroblastoma cell migration.

[Display omitted] • Low concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin could induce the directional migration of human neuroblastoma cells. • The upregulated genes were significantly enriched in the cell migration-related biological pathways. • The AhR-mediated mRNA and miR expressions involved in the axon guidance pathway played an important role. • The putative dioxin-responsive elements were present in the promoter regions of most genes and miRs in the axon guidance pathway. Tumor cell migration is affected by the aryl hydrocarbon receptor (AhR). However, the systematic molecular mechanisms underlying AhR-mediated migration of human neuroblastoma cells are not fully understood. To address this issue, we performed an integrative analysis of mRNA and microRNA (miR) expression profiles in human neuroblastoma SK- N -SH cells treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR. The cell migration was increased in a time- and concentration- dependent manner, and was blocked by AhR antagonist (CH223191). A total of 4,377 genes were differentially expressed after 24-hour-treatment with 10-10 M TCDD, of which the upregulated genes were significantly enriched in cell migration-related biological pathways. Thirty-four upregulated genes, of which 25 were targeted by 78 differentially expressed miRs, in the axon guidance pathway were experimentally confirmed, and the putative dioxin-responsive elements were present in the promoter regions of most genes (79 %) and miRs (82 %) in this pathway. Furthermore, two promigratory genes (CFL2 and NRP1) induced by TCDD was reversed by blockade of AhR. In conclusion, AhR-mediated mRNA-miR networks in the axon guidance pathway may represent a potential molecular mechanism of dioxin-induced directional migration of human neuroblastoma cells. [ABSTRACT FROM AUTHOR]