Betacellulin induces Slug-mediated down-regulation of E-cadherin and cell migration in ovarian cancer cells
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Jianfang Zhao1, Christian Klausen1, Xin Qiu1, Jung-Chien Cheng1, Hsun-Ming Chang1, Peter C.K. Leung1
1Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada
Peter C.K. Leung, email: [email protected]
Keywords: betacellulin, ovarian cancer, E-cadherin, cell migration, Slug
Received: October 26, 2015 Accepted: January 27, 2016 Published: April 23, 2016
Epithelial ovarian cancer is the leading cause of death among gynaecological cancers. Previous studies have demonstrated that epidermal growth factor receptor (EGFR) ligands can induce ovarian cancer cell invasion by down-regulating E-cadherin. Betacellulin is a unique member of the EGF family. It is overexpressed in a variety of cancers and is associated with reduced survival. However, the biological functions and clinical significance of betacellulin in ovarian cancer remain unknown. In the current study, we tested the hypothesis that betacellulin induces ovarian cancer cell migration by suppressing E-cadherin expression. Treatment of SKOV3 and OVCAR5 ovarian cancer cell lines with betacellulin down-regulated E-cadherin, but not N-cadherin. In addition, betacellulin treatment increased the expression of Snail and Slug, and these effects were completely blocked by pre-treatment with EGFR inhibitor AG1478. Interestingly, only knockdown of Slug reversed the down-regulation of E-cadherin by betacellulin. Betacellulin treatment induced the activation of both the MEK-ERK and PI3K-Akt signaling pathways, and it also significantly increased ovarian cancer cell migration. Importantly, the effects of betacellulin on E-cadherin, Slug and cell migration were attenuated by pre-treatment with either U0126 or LY294002. Our results suggest that betacellulin induces ovarian cancer migration and Slug-dependent E-cadherin down-regulation via EGFR-mediated MEK-ERK and PI3K-Akt signaling.
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