The International Journal of Biochemistry & Cell Biology 41 (2009) 1034–1045 Contents lists available at ScienceDirect The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of 61 integrin Michelle Colomiere a,d , Jock Findlay a,e , Leigh Ackland d , Nuzhat Ahmed a,b,c,∗ a Women’s Cancer Research Centre, Royal Women’s Hospital, Melbourne, Australia b Department of Obstetrics and Gynaecology, University of Melbourne, Australia c Department of Surgery, University of Melbourne, Australia d Centre for Cellular and Molecular Biology, Deakin University, Burwood, Melbourne, Australia e Prince Henry’s Institute of Medical Research, Melbourne, Australia article info Article history: Received 17 June 2008 Received in revised form 18 September 2008 Accepted 22 September 2008 Available online 27 September 2008 Keywords: Ovarian carcinoma Integrin Cadherin Migration Epithelial–mesenchymal transition abstract Peritoneal dissemination of ovarian carcinoma is mediated by epithelial–mesenchymal interconversions leading to the disruption of cell–cell contact and modulation of cell–extracellular matrix (ECM) inter- actions. The present study was designed to evaluate the effects of epidermal growth factor (EGF) as a modulator of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) sig- nalling and changes in integrin expression during the process similar to EMT. A fibroblastic morphology with reduced intercellular cell contacts and increased cell motility was observed in ovarian cancer cell lines in response to EGF and was concomitant with the up regulation of EMT-associated N-cadherin and vimentin expression. These changes were accompanied by an increase in 2, 6 and 1 integrin subunits and activation of JAK2 and STAT3 signalling which was suppressed by a specific JAK2 inhibitor. Consistent with the suppression of STAT3 activity, N-cadherin and vimentin expression were abrogated and was coherent with the loss of cell motility and the expression of 6 and 1 integrin subunits. Neutralizing antibodies against 6 and 1 subunits inhibited cancer cell migration. A strong correlation between the expression of N-cadherin, vimentin and JAK2/STAT3 levels were detected in high-grade ovarian tumors and was consistent with the previously reported enhanced expression of 6 integrin subunit in advanced tumors [Ahmed N, Riley C, Oliva K, Rice G, Quinn M. Ascites induces modulation of 61 integrin and uroki- nase plasminogen activator receptor expression and associated functions in ovarian carcinoma. British Journal of Cancer 2005;92:1475–85]. Our data incorporating the clinical samples and the cancer cell lines is the first to demonstrate that JAK2/STAT3 pathway may be one of the downstream events in EMT-like process and 61 integrin-mediated signalling in ovarian carcinomas. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction From a clinical perspective, epithelial ovarian cancer is the biggest challenge of all gynaecological cancers with 75% of the cases being presented at diagnosis with disseminated intraperitoneal metastases resulting in poor prognosis. Despite aggressive treat- ment, such as surgical cytoreduction and chemotherapy, more than two thirds of the patients succumb to the disease within 5 years (Cannistra, 2004). Unlike other solid tumors, lymphatic dissemina- ∗ Corresponding author at: Women’s Cancer Research Centre, Corner of Grattan Street and Flemington Road, Parkville, Victoria 3052, Australia. Tel.: +61 3 9344 2616. E-mail address: Nuzhat.Ahmed@thewomens.org.au (N. Ahmed). tion of ovarian cancer is rare, instead malignant ovarian epithelial cells expand as solid lesions exfoliating tumor cells in the peritoneal cavity which attach on the mesothelial layer of the peritoneum as single cells or multicellular aggregates (Burleson et al., 2006; Shield et al., 2007). In this context, cell–cell and cell–extracellular matrix (ECM) adhesion plays a critical role in the remodelling of the neoplastic ovarian epithelium implicating cadherins, integrins and associated signalling molecules in the intraperitoneal pro- gression of the disease. We and others have recently shown that epithelial–mesenchymal transition (EMT) is vital for the physiol- ogy of ovarian surface epithelium (Ahmed et al., 2006) and also for the growth and dissemination of ovarian cancer (Ahmed et al., 2007; Bagnato and Rosano, 2007) but the exact role of the pro- cess in the context of cell–cell and cell–ECM biology still remains elusive. 1357-2725/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2008.09.018