title: Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway.
abstract: BACKGROUND
  Infection with high-risk human papillomavirus (HR-HPV) genotypes, mainly HPV16 and HPV18, is a major risk factor for cervical cancer and responsible for its progression. While the transforming role of the HPV E6 and E7 proteins is more characterized, the molecular mechanisms of the oncogenic activity of the E5 product are still only partially understood, but appear to involve deregulation of growth factor receptor expression. Since the signaling of the transforming growth factor beta (TGFbeta) is known to play crucial roles in the epithelial carcinogenesis, aim of this study was to investigate if HPV16 E5 would modulate the TGF-BRII expression and TGFbeta/Smad signaling.
  
  
  RESULTS
  The HPV16 E5 mRNA expression pattern was variable in low-grade squamous intraepithelial lesions (LSIL), while homogeneously reduced in high-grade lesions (HSIL). Parallel analysis of TGFBRII mRNA showed that the receptor transcript levels were also variable in LSILs and inversely related to those of the viral protein. In vitro quantitation of the TGFBRII mRNA and protein in human keratinocytes expressing 16E5 in a dose-dependent and time-dependent manner showed a progressive down-modulation of the receptor. Phosphorylation of Smad2 and nuclear translocation of Smad4 were also decreased in E5-expressing cells stimulated with TGFbeta1.
  
  
  CONCLUSIONS
  Taken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis.
authors: Istitute Pasteur-Fondazione Cenci Bolognetti, Department of Clinical and Molecular Medicine, Sapienza University of Roma, and S. Andrea Hospital, Rome, Italy.
authors: Deborah
authors: D
authors: French
authors: Francesca
authors: F
authors: Belleudi
authors: Maria Vittoria
authors: MV
authors: Mauro
authors: Francesca
authors: F
authors: Mazzetta
authors: Salvatore
authors: S
authors: Raffa
authors: Vincenza
authors: V
authors: Fabiano
authors: Antonio
authors: A
authors: Frega
authors: Maria Rosaria
authors: MR
authors: Torrisi
mesh_terms: D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060787:Neoplasm Grading; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000086082:Viroporin Proteins
chemical_list: D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
references: J Cell Biol. 1988 Mar;106(3):761-71
references: 2450098
references: Cancer Metastasis Rev. 2012 Dec;31(3-4):553-68
references: 22714591
references: Mol Cancer. 2008 Jan 09;7:3
references: 18184435
references: Int J Oncol. 2007 Jul;31(1):69-79
references: 17549406
references: J Virol. 1995 Jul;69(7):4489-94
references: 7769709
references: J Virol. 2012 May;86(9):5341-51
references: 22357280
references: Gynecol Oncol. 2010 May;117(2 Suppl):S5-10
references: 20304221
references: Int J Cancer. 2005 Jan 10;113(2):276-83
references: 15386416
references: Nat Rev Cancer. 2007 Jan;7(1):11-22
references: 17186016
references: Hum Immunol. 2012 Sep;73(9):920-6
references: 22749886
references: J Clin Virol. 2011 Oct;52(2):79-83
references: 21767984
references: Cancer Res. 2004 Feb 15;64(4):1359-68
references: 14973079
references: Cancer Cell. 2007 Oct;12(4):313-27
references: 17936557
references: Biochim Biophys Acta. 2009 Jul;1793(7):1165-73
references: 19339207
references: Oncogene. 2011 Dec 15;30(50):4963-76
references: 21625213
references: Carcinogenesis. 2010 Nov;31(11):1905-12
references: 20819779
references: Mol Biol Cell. 2011 Mar 15;22(6):782-94
references: 21289094
references: Dis Markers. 2007;23(4):297-313
references: 17627064
references: Mol Cancer. 2011 Nov 11;10:140
references: 22078316
references: Cancer Cell. 2007 Oct;12(4):293-5
references: 17936552
references: Cancer Res. 2008 Sep 1;68(17):7200-9
references: 18757436
references: FEBS Lett. 2012 Jul 4;586(14):1921-8
references: 22710166
references: Nat Rev Cancer. 2010 Aug;10(8):550-60
references: 20592731
references: Int J Cancer. 1989 Apr 15;43(4):672-6
references: 2467886