Expression of the FGFR2 mesenchymal splicing variant in epithelial cells drives epithelial-mesenchymal transition
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Danilo Ranieri1, Benedetta Rosato1, Monica Nanni1, Alessandra Magenta1, Francesca Belleudi1,*, Maria Rosaria Torrisi1,2,*
1Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome, Italy
2Azienda Ospedaliera S. Andrea, Rome, Italy
*These authors have contributed equally to this work
Maria Rosaria Torrisi, e-mail: [email protected]
Francesca Belleudi, e-mail: [email protected]
Keywords: FGFR2, epithelial-mesenchymal transition, human keratinocytes
Received: September 01, 2015 Accepted: December 07, 2015 Published: December 21, 2015
The FGFRs are receptor tyrosine kinases expressed by tissue-specific alternative splicing in epithelial IIIb or mesenchymal IIIc isoforms. Deregulation of FGF/FGFR signaling unbalances the epithelial-stromal homeostasis and may lead to cancer development. In the epithelial-context, while FGFR2b/KGFR acts as tumor suppressor, FGFR2c appears to play an oncogenic role. Based on our recent observation that the switching of FGFR2b versus FGFR2c induces EMT, here we investigated the biological outcome of the ectopic expression of FGFR2c in normal human keratinocytes. Morphological analysis showed that, differently from FGFR2b overexpression, the forced expression and activation of FGFR2c drive the epithelial cells to acquire a mesenchymal-like shape and actin reorganization. Moreover, the appearance of invasiveness and anchorage-independent growth ability in FGFR2c transfected keratinocytes was consistent with the potential tumorigenic role proposed for this receptor variant. Biochemical and molecular approaches revealed that the observed phenotypic changes were accompanied by modulation of EMT biomarkers and indicated the involvement of EMT transcription factors and miRs. Finally, the analysis of the expression pattern of discriminating markers strongly suggested that activation of FGFR2c triggers a process corresponding to the initiation of the pathological type III EMT, but not to the more physiological type II EMT occurring during FGFR2b-mediated wound healing.
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