title: Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis.
abstract: OBJECTIVE
  Human Hepatocellular Carcinoma (HCC) is the fifth most frequent neoplasm worldwide and the most serious complication of long-standing chronic liver diseases (CLD). Its development is associated with chronic inflammation and sustained oxidative stress. Deregulation of apurinic apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1), a master regulator of cellular response to oxidative stress, has been associated with poor prognosis in several cancers including HCC.
  
  
  METHODS
  In the present study we investigated the APE1/Ref-1 mRNA levels in cirrhotic and HCC tissues obtained during HCC resection. The possible protective role of APE1/Ref-1 against oxidative stress and apoptosis was evaluated in vitro in immortalized human hepatocytes (IHH) over-expressing APE1/Ref-1.
  
  
  RESULTS
  APE1/Ref-1 was up-regulated in HCC, regulation occurring at the transcriptional level. APE1/Ref-1 mRNA content increased with the progression of liver disease with the transcriptional up-regulation present in cirrhosis significantly increased in HCC. The up-regulation was higher in the less differentiated cancers. In vitro, over-expression of APE1/Ref-1 in normal hepatocytes conferred cell protection against oxidative stress and it was associated with BAX inhibition and escape from apoptosis.
  
  
  CONCLUSIONS
  APE1/Ref-1 is up-regulated in HCC and this over-expression correlates with cancer aggressiveness. The up-regulation occurs at the transcriptional level and it is present in the earliest phases of hepatocarcinogenesis. The APE-1/Ref-1 over-expression is associated with hepatocyte survival and inhibits BAX activation and apoptosis. These data suggest a possible role of APE1/Ref-1 over-expression both in hepatocyte survival and HCC development calling attention to this molecule as a promising marker for HCC diagnosis and treatment.
authors.affiliation: FIF- Fondazione Italiana Fegato Area Science Park Basovizza. Trieste, Italia.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Di Maso
authors.affiliation: FIF- Fondazione Italiana Fegato Area Science Park Basovizza. Trieste, Italia.
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Mediavilla
authors.affiliation: Dipartimento Scienze Mediche e Biologiche, Università di Udine. Udine, Itala.
authors.forename: Carlo
authors.initials: C
authors.lastname: Vascotto
authors.affiliation: Chirurgia Generale 2 Centro Trapianto Fegato Universitá Torino. Torino, Italia.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lupo
authors.affiliation: Dipartimento Scienze Mediche e Biologiche, Università di Udine. Udine, Itala.
authors.forename: Umberto
authors.initials: U
authors.lastname: Baccarani
authors.affiliation: Dipartimento Scienze Mediche e Biologiche, Università di Udine. Udine, Itala.
authors.forename: Claudio
authors.initials: C
authors.lastname: Avellini
authors.affiliation: FIF- Fondazione Italiana Fegato Area Science Park Basovizza. Trieste, Italia.|Dipartimento Scienze Mediche e Biologiche, Università di Udine. Udine, Itala.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.affiliation: FIF- Fondazione Italiana Fegato Area Science Park Basovizza. Trieste, Italia.|Dipartimento Scienze Mediche, Università di Trieste. Trieste, Italia.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiribelli
authors.affiliation: FIF- Fondazione Italiana Fegato Area Science Park Basovizza. Trieste, Italia.|Dipartimento Scienze Mediche, Università di Trieste. Trieste, Italia.
authors.forename: Lory Saveria
authors.initials: LS
authors.lastname: Crocè
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase