Zonula occludens‐1/NF‐κB/CXCL8: a new regulatory axis for tumor angiogenesis. Issue 4 (17th January 2017)

• Record Type: Journal Article
• Authors: Lesage, Julien; Suarez‐Carmona, Meggy; Neyrinck‐Leglantier, Deborah; Grelet, Simon; Blacher, Silvia; Hunziker, Walter; Birembaut, Philippe; Noël, Agnes; Nawrocki‐Raby, Béatrice; Gilles, Christine; Polette, Myriam
• Is Part Of: FASEB journal. Volume 31:Issue 4(2017)
• Page Start: 1668
• Page End: 1677
• Publication Date: 2017-01-17
• Subjects: EMT -- tumor progression -- ZO‐1 -- IL‐8; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201600890R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : Zonula occludens‐1 (ZO‐1) is a submembrane scaffolding protein that may display proinvasive functions when it relocates from tight junctions into the cytonuclear compartment. This article examines the functional involvement of ZO‐1 in CXCL8/IL‐8 chemokine expression in lung and breast tumor cells. ZO‐1 small interfering RNA and cDNA transfection experiments emphasized regulation of CXCL8/IL‐8 expression via a cytonuclear pool of ZO‐1. Luciferase reporter assays highlighted a 173‐bp region of CXCL8/IL‐8 promoter that responded to ZO‐1. Moreover, by using mutated promoter constructs, we identified a NF‐κB site as critical in this activation. Furthermore, NF‐κB pathway signaling analysis revealed both IκBα and p65 phosphorylation in ZO‐1‐overexpressing cells, and subsequent p65 silencing validated its requirement for CXCL8/IL‐8 induction. Investigation of the functional implication of this regulatory axis next showed the proangiogenic activity of ZO‐1 in both ex viv o and in vivo angiogenesis assays. Finally, we found that non–small‐cell lung carcinoma that presented a cytonuclear ZO‐1 pattern was significantly more angiogenic that that without detectable cytonuclear ZO‐1 expression. Taken together, our results demonstrate that ZO‐1 regulates CXCL8/IL‐8 expression via the NF‐κB signaling pathway and its p65 subunit, which subsequently modulates the transcription of IL‐8. We also provide evidence of a newly identified regulatory pathway that could promote angiogenesis. Thus, our results support the concept that the ZO‐1 shuttle from the cell junction to the cytonuclear compartment may affect both the intrinsic invasive properties of tumor cells and the establishment of the protumoral microenvironment. —Lesage, J., Suarez‐Carmona, M., Neyrinck‐Leglantier, D., Grelet, S., Blacher, S., Hunziker, W., Birembaut, P., Noël, A., Nawrocki‐Raby, B., Gilles, C., Polette, M. Zonula occludens‐1/NF‐κB/CXCL8: a new regulatory axis for tumor angiogenesis. FASEB J . 31, 1678–1688 (2017) www.fasebj.org