title: Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation.
abstract: OBJECTIVE
  Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines.
  
  
  METHODS
  HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells.
  
  
  RESULTS
  The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation.
  
  
  CONCLUSIONS
  The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: González
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.
authors.forename: Ángel J
authors.initials: ÁJ
authors.lastname: De la Rosa
authors.affiliation: Department of Cancer Studies, CRUK Leicester Cancer, Leicester, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rufini
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: Rodríguez-Hernández
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Navarro-Villarán
authors.affiliation: Pathology Department, IMIBIC/Hospital University "Reina Sofía", Córdoba, Spain.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Marchal
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Pereira
authors.affiliation: Gastroenterology Department, IMIBIC/Hospital University "Reina Sofía", Córdoba, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.affiliation: Gastroenterology and Hepatology Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Schilling
authors.affiliation: Gastroenterology Department, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascasio-Acevedo
authors.affiliation: Gastroenterology Department, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Ferrer-Ríos
authors.affiliation: Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gómez-Bravo
authors.affiliation: Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Padillo
authors.affiliation: Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Jordi
authors.identifier: http://orcid.org/0000-0002-6744-1121
authors.initials: J
authors.lastname: Muntané
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006509:Hepatitis B / Q000150:complications; D006515:Hepatitis B virus / Q000302:isolation & purification; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D020033:Protein Isoforms / Q000235:genetics; D053218:Receptors, Death Domain / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000072160:Tumor Protein p73 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D053218:Receptors, Death Domain; C115051:TP63 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins