title: HPV16 E5 expression induces switching from FGFR2b to FGFR2c and epithelial-mesenchymal transition.
abstract: The E5 oncoprotein of the human papillomavirus type 16 (HPV16 E5) deregulates epithelial homeostasis through the modulation of receptor tyrosine kinases and their signaling. Accordingly, the fibroblast growth factor receptor 2b (FGFR2b/KGFR), epithelial splicing transcript variant of the FGFR2, is down-modulated by the viral protein expression, leading to impairment of keratinocyte differentiation. Here, we report that, in cell models of transfected human keratinocytes as well as in cervical epithelial cells containing episomal HPV16, the down-regulation of FGFR2b induced by 16E5 is associated with the aberrant expression of the mesenchymal FGFR2c isoform as a consequence of splicing switch: in fact, quantitative RT-PCR analysis showed that this molecular event is transcriptionally regulated by the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) and is able to produce effects synergistic with those caused by TGFβ treatment. Immunofluorescence analysis revealed that this altered FGFR2 splicing leads to changes in the specificity for the ligands FGFs and in the cellular response, triggering epithelial-mesenchymal transition (EMT). Through 16E5 or FGFR2 silencing as well as inhibition of FGFR2 activity we demonstrated the direct role of the viral protein in the receptor isoform switching and EMT, suggesting that these early molecular events during HPV infection might represent additional mechanisms driving cervical transformation and tumor progression.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Ranieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magenta
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
mesh_terms: D002460:Cell Line; D002584:Cervix Uteri / Q000166:cytology / Q000378:metabolism / Q000821:virology; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005786:Gene Expression Regulation; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D016601:RNA-Binding Proteins / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D000086082:Viroporin Proteins
chemical_list: D007527:Isoenzymes; D009856:Oncogene Proteins, Viral; D016601:RNA-Binding Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2; C539364:ESRP1 protein, human; C539365:ESRP2 protein, human; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C496353:FGFR2 protein, human
keywords: FGFR; HPV16 E5; epithelial-mesenchymal transition; human keratinocytes