HPV16 E5 and KGFR/FGFR2b interplay in differentiating epithelial cells.

Valeria Purpura (1) , Francesca Belleudi (1) , Silvia Caputo (1) , Maria Rosaria Torrisi (1, 2)

1 Department of Molecular Medicine
2 Azienda Ospedaliera S. Andrea

The E5 oncogenic protein of the human papillomavirus type 16 (HPV16 E5) cooperates in epithelial transformation perturbing the behaviour of differentiating suprabasal cells. Among the receptor tyrosine kinases deregulated by 16E5 expression, the key paracrine mediator of epithelial homeostasis keratinocyte growth factor receptor (KGFR/FGFR2b) is altered in its signaling and endocytic traffic in undifferentiated keratinocytes expressing 16E5 and it would represent a major target of the viral protein in differentiated cells. With the aim to specifically address the possible interplay of 16E5 with KGFR/FGFR2b in cells already committed to differentiation, we took advantage of an in vitro model for forced overexpression or depletion of KGFR in E5 expressing human keratinocytes under synchronous waves of differentiation. Quantitative RT-PCR, biochemical and immunofluorescence analysis showed that KGFR down-modulation is responsible for a E5-mediated decrease of the early differentiation marker K1 and that the receptor re-expression as well as triggering of its kinase activity and signaling are able to efficiently counteract the impairment of differentiation, providing a further demonstration of the tumor-suppressive role of KGFR in the new unexplored context of HPV16 E5-mediated carcinogenesis. In addition, KGFR induced a ligand-dependent decrease of p63 through a miR-203 independent mechanism and this effect was blocked by inhibition of the PI3K/Akt signaling, which is the main pathway involved in KGFR-dependent keratinocyte differentiation, suggesting that alterations of the KGFR/p63 crosstalk are responsible for the impairment of keratinocyte differentiation induced by 16E5 and that the opposite tumor-suppressive action of KGFR and oncogenic role of E5 might both involve p63.

Domaines: Cancer

Valeria Purpura, Francesca Belleudi, Silvia Caputo, Maria Rosaria Torrisi. HPV16 E5 and KGFR/FGFR2b interplay in differentiating epithelial cells.. Oncotarget, 2013, 4 (2), pp.192-205. ⟨10.18632/oncotarget.803⟩. ⟨pasteur-01053842⟩