Cargando…

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JA...

Descripción completa

Detalles Bibliográficos
Autores principales: Colomiere, M, Ward, A C, Riley, C, Trenerry, M K, Cameron-Smith, D, Findlay, J, Ackland, L, Ahmed, N
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634691/
https://www.ncbi.nlm.nih.gov/pubmed/19088723
http://dx.doi.org/10.1038/sj.bjc.6604794
_version_ 1782164144906043392
author Colomiere, M
Ward, A C
Riley, C
Trenerry, M K
Cameron-Smith, D
Findlay, J
Ackland, L
Ahmed, N
author_facet Colomiere, M
Ward, A C
Riley, C
Trenerry, M K
Cameron-Smith, D
Findlay, J
Ackland, L
Ahmed, N
author_sort Colomiere, M
collection PubMed
description Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer.
format Text
id pubmed-2634691
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-26346912010-01-13 Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas Colomiere, M Ward, A C Riley, C Trenerry, M K Cameron-Smith, D Findlay, J Ackland, L Ahmed, N Br J Cancer Molecular Diagnostics Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer. Nature Publishing Group 2009-01-13 2008-12-16 /pmc/articles/PMC2634691/ /pubmed/19088723 http://dx.doi.org/10.1038/sj.bjc.6604794 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Molecular Diagnostics
Colomiere, M
Ward, A C
Riley, C
Trenerry, M K
Cameron-Smith, D
Findlay, J
Ackland, L
Ahmed, N
Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title_full Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title_fullStr Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title_full_unstemmed Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title_short Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas
title_sort cross talk of signals between egfr and il-6r through jak2/stat3 mediate epithelial–mesenchymal transition in ovarian carcinomas
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634691/
https://www.ncbi.nlm.nih.gov/pubmed/19088723
http://dx.doi.org/10.1038/sj.bjc.6604794
work_keys_str_mv AT colomierem crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT wardac crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT rileyc crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT trenerrymk crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT cameronsmithd crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT findlayj crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT acklandl crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas
AT ahmedn crosstalkofsignalsbetweenegfrandil6rthroughjak2stat3mediateepithelialmesenchymaltransitioninovariancarcinomas