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Title

EGFR signaling upregulates expression of microsomal prostaglandin e synthase-1 in cancer cells leading to enhanced tumorigenicity

AuthorsDonnini, Sandra; Finetti, Federica; Terzuoli, Erika; Giachetti, Antonio; Íñiguez, Miguel Ángel ; Hanaka, Hiromi; Fresno, Manuel ; Radmark, Olof; Ziche, Marina
KeywordsProstaglandinE-2
mPGES-1
Epidermal growth factor
Egr-1
Vimentin
E-cadherin
Issue Date2012
PublisherNature Publishing Group
CitationOncogene 31: 3457- 3466 (2012)
AbstractIn this report we describe the contribution of prostaglandin E 2 (PGE 2) derived from the inducible microsomal PGE-synthase type-1 (mPGES-1) to the epidermal growth factor receptor (EGFR) oncogenic drive in tumor epithelial cells and in tumor-bearing mice. EGFR stimulation upregulated expression of mPGES-1 in HT-29, A431 and A549 cancer cells. Egr-1, a transcription factor induced by EGF, mediated this response. The Egr-1 rise provoked the overexpression of mPGES-1 messenger and protein, and enhanced PGE 2 formation. These changes were suppressed either by silencing Egr-1, or by upstream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was silenced or knocked down. EGF-induced mPGES-1 overexpression in epithelial cell reduced E-cadherin expression, whereas enhancing that of vimentin, suggesting an incipient mesenchymal phenotype. Additionally, inhibiting the EGFR in mice bearing the A431 tumor, the mPGES-1 expression and the tumor growth, exhibited a parallel decline. In conclusion, these findings provide novel evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for controlling the vicious association. © 2012 Macmillan Publishers Limited All rights reserved.
URIhttp://hdl.handle.net/10261/112345
DOI10.1038/onc.2011.503
Identifiersdoi: 10.1038/onc.2011.503
issn: 0950-9232
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