Research Papers:

Sprouty2 inhibits amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells

Jung-Chien Cheng _, Hsun-Ming Chang, Siyuan Xiong, Wai-Kin So and Peter C. K. Leung

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Oncotarget. 2016; 7:81645-81660. https://doi.org/10.18632/oncotarget.13162

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Jung-Chien Cheng1,*, Hsun-Ming Chang1,*, Siyuan Xiong1, Wai-Kin So1, Peter C. K. Leung1

1Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

*These authors have contributed equally to this work

Correspondence to:

Peter C.K. Leung, email: [email protected]

Keywords: amphiregulin, E-cadherin, ovarian cancer, sprouty2

Received: August 12, 2016     Accepted: October 22, 2016     Published: November 07, 2016


Similar to Drosophila Sprouty (SPRY), mammalian SPRY proteins inhibit the receptor tyrosine kinase-mediated activation of cellular signaling pathways. SPRY2 expression levels have been shown to be down-regulated in human ovarian cancer, and patients with low SPRY2 expression have significantly poorer survival than those with high SPRY2 expression. In addition, epidermal growth factor receptor (EGFR) is overexpressed in human ovarian cancer and is associated with more aggressive clinical behavior and a poor prognosis. Amphiregulin (AREG), the most abundant EGFR ligand in ovarian cancer, binds exclusively to EGFR and stimulates ovarian cancer cell invasion by down-regulating E-cadherin expression. However, thus far, the roles of SPRY2 in AREG-regulated E-cadherin expression and cell invasion remain unclear. In the present study, we show that treatment with AREG up-regulated SPRY2 expression by activating the EGFR-mediated ERK1/2 signaling pathway in two human ovarian cancer cell lines, SKOV3 and OVCAR5. In addition, overexpression of SPRY2 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the induction of the E-cadherin transcriptional repressor, Snail. Moreover, SPRY2 overexpression attenuated AREG-stimulated cell invasion and proliferation. This study reveals that SPRY2 acts as a tumor suppressor in human ovarian cancer and illustrates the underlying mechanisms that can be used as possible targets for the development of novel therapeutics.

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