title: HPV16 E5 and KGFR/FGFR2b interplay in differentiating epithelial cells.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Purpura
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.forename: Silvia
authors.initials: S
authors.lastname: Caputo
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Torrisi
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000086082:Viroporin Proteins
chemical_list: D009856:Oncogene Proteins, Viral; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051497:Receptor, Fibroblast Growth Factor, Type 2; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
references.citation: Cancer Res. 2004 Feb 15;64(4):1359-68
references.pmid: 14973079
references.citation: Oncogene. 2011 Dec 15;30(50):4963-76
references.pmid: 21625213
references.citation: J Virol. 1993 Oct;67(10):6170-8
references.pmid: 7690419
references.citation: Oncogene. 2008 Apr 17;27(18):2532-41
references.pmid: 17982485
references.citation: J Gen Virol. 2010 Feb;91(Pt 2):521-30
references.pmid: 19812262
references.citation: Cell Growth Differ. 2000 Nov;11(11):607-14
references.pmid: 11095249
references.citation: J Virol. 2010 May;84(10):5212-21
references.pmid: 20219920
references.citation: EMBO J. 2007 Mar 7;26(5):1268-78
references.pmid: 17304214
references.citation: Cancer Res. 1997 Dec 1;57(23):5369-78
references.pmid: 9393762
references.citation: Oncogene. 2003 Aug 11;22(33):5201-7
references.pmid: 12910257
references.citation: J Invest Dermatol. 2001 Apr;116(4):623-8
references.pmid: 11286634
references.citation: J Biol Chem. 2007 Mar 2;282(9):6126-35
references.pmid: 17197440
references.citation: J Cell Physiol. 1990 Aug;144(2):326-32
references.pmid: 1696274
references.citation: Nat Rev Cancer. 2010 Feb;10(2):116-29
references.pmid: 20094046
references.citation: J Cell Biol. 2010 Mar 22;188(6):935-52
references.pmid: 20308431
references.citation: Cell Mol Life Sci. 2008 Oct;65(20):3126-33
references.pmid: 18560758
references.citation: Cancer Res. 2010 May 15;70(10):4081-91
references.pmid: 20442284
references.citation: J Cell Biol. 1988 Mar;106(3):761-71
references.pmid: 2450098
references.citation: Microbiol Mol Biol Rev. 2004 Jun;68(2):362-72
references.pmid: 15187189
references.citation: J Cell Biol. 1995 Apr;129(2):357-66
references.pmid: 7721940
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11999-2004
references.pmid: 17626181
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11336-40
references.pmid: 11562460
references.citation: EMBO Mol Med. 2012 Mar;4(3):192-205
references.pmid: 22247000
references.citation: Mol Cancer. 2011 Nov 11;10:140
references.pmid: 22078316
references.citation: Cancer Res. 2003 May 15;63(10):2351-7
references.pmid: 12750249
references.citation: J Exp Med. 1995 Nov 1;182(5):1369-76
references.pmid: 7595207
references.citation: Cancer Res. 2007 Jul 1;67(13):6106-12
references.pmid: 17616666
references.citation: Nature. 2008 Mar 13;452(7184):225-9
references.pmid: 18311128
references.citation: FASEB J. 2006 Feb;20(2):395-7
references.pmid: 16354720
references.citation: PLoS One. 2011;6(9):e24194
references.pmid: 21957444
references.citation: Int J Cancer. 2005 Jan 10;113(2):276-83
references.pmid: 15386416
references.citation: PLoS One. 2011;6(7):e21646
references.pmid: 21747943
references.citation: Cell Death Differ. 2008 Jul;15(7):1187-95
references.pmid: 18483491
references.citation: Nat Rev Cancer. 2010 Aug;10(8):550-60
references.pmid: 20592731
references.citation: Int J Cancer. 1989 Apr 15;43(4):672-6
references.pmid: 2467886