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

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 epithelialmesenchymal 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 b-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.

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

“…The expression of Zeb1, Zeb2, Snail and Slug have all been implicated in EMT induction and the acquisition of an invasive cell phenotype, as reviewed in [24]. Altered expression of FGF-1 and FGF-2 have also been associated with a dedifferentiated and invasive cell phenotype [27], and there is evidence that factors such as TGF-β [28,29] and epidermal growth factor (EGF) [28,30] induce EMT. Our findings support the paradigm that epithelial and mesenchymal tumor cells are present in primary murine mammary tumors and that phenotypic plasticity can be induced in vitro by external factors including FGF-1 and TGF-β.…”

Inflammation and ovarian cancer

“…These data suggest that the activated status of STAT3 in high-grade EOC 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 et al, 2009). In addition to STAT3 also the Ras protein can be activated in response to IL-6.…”

Identification of Genes and MicroRNAs Involved in Ovarian Carcinogenesis

“…The overall 5-year mortality of ovarian cancer is about 70%, lower than other types of gynecological cancer, although various therapeutic approaches are followed in clinical practice (Colomiere et al, 2009). This is mainly because most cases are not diagnosed until the disease is at an advanced stage (Ono et al, 2000).…”