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.