title: Egr-1 mediates epidermal growth factor-induced downregulation of E-cadherin expression via Slug in human ovarian cancer cells.
abstract: Loss of the cell adhesion protein E-cadherin increases the invasive capability of ovarian cancer cells. We have previously shown that epidermal growth factor (EGF) downregulates E-cadherin and induces ovarian cancer cell invasion through the H(2)O(2)/p38 MAPK-mediated upregulation of the E-cadherin transcriptional repressor Snail. However, the molecular mechanisms underlying the EGF-induced downregulation of E-cadherin are not fully understood. In the current study, we demonstrated that treatment of two ovarian cancer cell lines, SKOV3 and OVCAR5, with EGF induced the expression of the transcription factor Egr-1, and this induction was abolished by small interfering RNA (siRNA)-mediated depletion of the EGF receptor. EGF-induced Egr-1 expression required the activation of the ERK1/2 and PI3K/Akt signaling pathways and was unrelated to EGF-induced H(2)O(2) production and activation of the p38 MAPK pathway. Moreover, depletion of Egr-1 with siRNA abolished the EGF-induced downregulation of E-cadherin and increased cell invasion. Interestingly, siRNA depletion of Egr-1 attenuated the EGF-induced expression of Slug, but not that of Snail. Moreover, chromatin immunoprecipitation (ChIP) analysis showed that Slug is a target gene of Egr-1. These results provide evidence that Egr-1 is a mediator that is involved in the EGF-induced downregulation of E-cadherin and increased cell invasion. Our results also demonstrate that EGF activates two independent signaling pathways, which are the H(2)O(2)/p38 MAPK-mediated upregulation of Snail expression and the Egr-1-mediated upregulation of Slug expression. These two signaling pathways contribute to the EGF-induced downregulation of E-cadherin, which subsequently increases the invasive capability of ovarian cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: J-C
authors.initials: JC
authors.lastname: Cheng
authors.forename: H-M
authors.initials: HM
authors.lastname: Chang
authors.forename: P C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D015820:Cadherins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors