Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells
- 266 Downloads
Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down-regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression.
KeywordsAmphiregulin E-cadherin Ovarian cancer Sprouty4
We also thank Dr. Graeme R. Guy (The Institute of Molecular and Cell Biology, Singapore) for the generous gifts of pXJ40-FLAG and FLAG-SPRY4 plasmids. This work was supported by an operating grant from the Canadian Institutes of Health Research (#143317) to P.C.K.L. P.C.K.L. is a Scientist Level 3 of the Child and Family Research Institute.
Compliance with ethical standards
Conflicts of interest
This work was supported by an operating grant from the Canadian Institutes of Health Research (#143317) to P.C.K.L.
- 17.Inoue Y, Miyamoto S, Fukami T, Shirota K, Yotsumoto F, Kawarabayashi T. Amphiregulin is much more abundantly expressed than transforming growth factor-alpha and epidermal growth factor in human follicular fluid obtained from patients undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2009;91:1035–41.CrossRefPubMedGoogle Scholar
- 29.Tennis MA, Van Scoyk MM, Freeman SV, Vandervest KM, Nemenoff RA, Winn RA. Sprouty-4 inhibits transformed cell growth, migration and invasion, and epithelial-mesenchymal transition, and is regulated by Wnt7A through PPARgamma in non-small cell lung cancer. Mol Cancer Res: MCR. 2010;8:833–43.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Zhang Q, Wei T, Shim K, Wright K, Xu K, Palka-Hamblin HL, Jurkevich A, Khare S: Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition. Oncogene 2015.Google Scholar