Sprouty2 inhibits amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells.
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.
Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Jung-Chien
JC
Cheng
Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Hsun-Ming
HM
Chang
Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Siyuan
S
Xiong
Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Wai-Kin
WK
So
Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Peter C K
PC
Leung
D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D011799:Quinazolines; C485561:SPRY2 protein, human; D000071250:Snail Family Transcription Factors; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
E-cadherin; amphiregulin; ovarian cancer; sprouty2