title: Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma: possible prognostic significance.
abstract: 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.
authors.affiliation: Centro Studi Fegato, AREA Science Park and University of Trieste, Trieste, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Di Maso
authors.forename: Claudio
authors.initials: C
authors.lastname: Avellini
authors.forename: Lory Saveria
authors.initials: LS
authors.lastname: Crocè
authors.forename: Natalia
authors.initials: N
authors.lastname: Rosso
authors.forename: Franco
authors.initials: F
authors.lastname: Quadrifoglio
authors.forename: Laura
authors.initials: L
authors.lastname: Cesaratto
authors.forename: Erika
authors.initials: E
authors.lastname: Codarin
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bedogni
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Beltrami
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiribelli
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D008954:Models, Biological; D011379:Prognosis; D012044:Regression Analysis; D013347:Subcellular Fractions / Q000201:enzymology; D016019:Survival Analysis
chemical_list: C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase