EMAIL THIS PAGE TO A FRIEND

British journal of cancer

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


PMID 19088723

Abstract

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 beta-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.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SRP5172
Catenin β, GST tagged human, recombinant, expressed in baculovirus infected Sf9 cells, ≥70% (SDS-PAGE), buffered aqueous glycerol solution
M3769 Medium 199, Modified, with Earle′s salts, without L-glutamine, sodium bicarbonate, and phenol red, powder, suitable for cell culture
M0393 Medium 199, With Hanks′ salts and L-glutamine, without sodium bicarbonate, powder, suitable for cell culture
M2520 Medium 199, HEPES Modification, with Earle′s salts, L-glutamine and 25 mM HEPES, without sodium bicarbonate, powder, suitable for cell culture
M0650 Medium 199, 10 ×, With Earle′s salts, without L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
M7653 Medium 199, With Hanks′ salts and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
M7528 Medium 199, HEPES Modification, with Earle′s salts, 25 mM HEPES and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
M9163 Medium 199, 10 ×, With Hanks′ salts, without L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
M2154 Medium 199, With Earle′s salts and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
M4530 Medium 199, With Earle′s salts, L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
M5017 Medium 199, With Earle′s salts and L-glutamine, without sodium bicarbonate, powder, suitable for cell culture