Zonula occludens-1/NF-κB/CXCL8: a new regulatory axis for tumor angiogenesis.
FASEB J
; 31(4): 1678-1688, 2017 04.
Article
em En
| MEDLINE
| ID: mdl-28057697
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 vivo 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
/
Interleucina-8
/
NF-kappa B
/
Proteína da Zônula de Oclusão-1
/
Neovascularização Patológica
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
França