Abstract
In this report we describe the contribution of prostaglandin E2 (PGE2) 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 PGE2 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.
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Acknowledgements
We thank Dr MD Díaz-Muñoz for the construction of mPGES-1 plasmids. This work has received financial support from the Associazione Italiana della Ricerca sul Cancro (AIRC) IG10731 (MZ), Istituto Toscano Tumori (ITT) (SD), Comunidad de Madrid S-SAL2006/0015, Ministerio de Ciencia e Innovación SAF2010-18733 (MF), Ministerio de Ciencia e Innovación BFU2010-21055 (MAI).
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Donnini, S., Finetti, F., Terzuoli, E. et al. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene 31, 3457–3466 (2012). https://doi.org/10.1038/onc.2011.503
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DOI: https://doi.org/10.1038/onc.2011.503
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