Molecular Medicine

, Volume 13, Issue 1–2, pp 89–96 | Cite as

Subcellular Localization of APE1/Ref-1 in Human Hepatocellular Carcinoma: Possible Prognostic Significance

  • Vittorio Di Maso
  • Claudio Avellini
  • Lory Saveria Crocè
  • Natalia Rosso
  • Franco Quadrifoglio
  • Laura Cesaratto
  • Erika Codarin
  • Giorgio Bedogni
  • Carlo Alberto Beltrami
  • Gianluca Tell
  • Claudio Tiribelli
Research Article


APE1/Ref-1, normally localized in the nucleus, is a regulator of the cellular response to oxidative stress. Cytoplasmic localization has been observed in several tumors and correlates with a poor prognosis. Because no data are available on liver tumors, we investigated APE1/Ref-1 subcellular localization and its correlation with survival in 47 consecutive patients undergoing hepatocellular carcinoma (HCC) resection. APE1/Ref-1 expression was determined by immunohistochemistry in HCC and surrounding liver cirrhosis (SLC) and compared with normal liver tissue. Survival probability was evaluated using Kaplan-Meier curves (log-rank test) and Cox regression. Cytoplasmic expression of APE1/Ref-1 was significantly higher in HCC than in SLC (P = 0.00001); normal liver showed only nuclear reactivity. Patients with poorly differentiated HCC showed a cytoplasmic expression three times higher than those with well-differentiated HCC (P = 0.03). Cytoplasmic localization was associated with a median survival time shorter than those with negative cytoplasmic reactivity (0.44 compared with 1.64 years, P = 0.003), and multivariable analysis confirmed that cytoplasmic APE1/Ref-1 localization is a predictor of survival. Cytoplasmic expression of APE1/Ref-1 is increased in HCC and is associated with a lower degree of differentiation and a shorter survival time, pointing to the use of the cytoplasmic localization of APE1/Ref-1 as a prognostic marker for HCC.



This study was supported by grants from Italian Ministry of Research and University (MIUR), Rome, Italy (FIST 01 to C.T.), AIRC (regional grant from FVG to C.T. and G.T.), and the Liver Research Center, Trieste (FCRT to C.T.). The support by a grant from MIUR (PRIN 2005 to G.T.) is also acknowledged.


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Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Vittorio Di Maso
    • 1
  • Claudio Avellini
    • 2
  • Lory Saveria Crocè
    • 1
  • Natalia Rosso
    • 1
  • Franco Quadrifoglio
    • 3
  • Laura Cesaratto
    • 3
  • Erika Codarin
    • 3
  • Giorgio Bedogni
    • 1
  • Carlo Alberto Beltrami
    • 2
  • Gianluca Tell
    • 3
  • Claudio Tiribelli
    • 1
  1. 1.Centro Studi FegatoAREA Science Park and University of TriesteTriesteItaly
  2. 2.Dipartimento di Scienze Mediche e MorfologicheUniversity of UdineUdineItaly
  3. 3.Dipartimento di Scienze e Tecnologie BiomedicheUniversity of UdineUdineItaly

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