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 (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.
Colomiere
M
M
Women's Cancer Research Centre, Royal Women's Hospital, Melbourne, Australia.
Ward
A C
AC
Riley
C
C
Trenerry
M K
MK
Cameron-Smith
D
D
Findlay
J
J
Ackland
L
L
Ahmed
N
N
D015703:Antigens, CD / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology*; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000502:physiology*; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis; D008648:Mesoderm / Q000166:cytology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D020239:Receptor Cross-Talk / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D014746:Vimentin / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014746:Vimentin; D051176:beta Catenin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2