American Association for Cancer Research, Inc. (AACR)
[en] ZO-1 ; CXCL8/IL-8 ; Breast cancer
[en] Accumulating data now suggest that ZO-1, once delocalized from tight junctions, could be implicated in the regulation of tumor promoting genes. Because of their major implication in different steps of tumor progression, we investigated here the influence of ZO-1 on chemokines expression in breast cancer cells. Using GeneArray analysis to compare chemokine mRNA expression in breast tumor cells transfected with a siRNA against ZO-1, we identified CXCL-8/IL-8 as a major potential target of ZO-1 signaling, being strongly downregulated following ZO-1 siRNA transfection. Examining further the relationship between ZO-1 and IL-8, we first demonstrated that CXCL8/IL-8 expression correlates with a relocalization of ZO-1 in several breast cancer cell lines. Moreover, CXCL8/IL-8 is downregulated in invasive BT549 cells transfected with 3 different ZO-1 siRNA and overexpressed in non-invasive BT20 and SKBR3 cells transfected with vectors expressing ZO-1. We also provide evidence for an activation of the CXCL8/IL-8 promoter by ZO-1. Finally, we demonstrate that the regulation of CXCL8/IL-8 by ZO-1 is independent of the beta-catenin pathway. Our results thus clearly demonstrate an implication of ZO-1 in CXCL8/IL-8 regulation. Because of the major implications of CXCL8/IL-8 in tumor invasion, such a regulation could play an important role in breast cancer progression.