Di Maso Vittorio, Avellini Claudio, Crocè Lory Saveria, Rosso Natalia, Quadrifoglio Franco, Cesaratto Laura, Codarin Erika, Bedogni Giorgio, Beltrami Carlo Alberto, Tell Gianluca, Tiribelli Claudio
Centro Studi Fegato, AREA Science Park and University of Trieste, Trieste, Italy.
Mol Med. 2007 Jan-Feb;13(1-2):89-96. doi: 10.2119/2006-00084.dimaso.
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.
APE1/Ref-1通常定位于细胞核，是细胞对氧化应激反应的调节因子。在几种肿瘤中观察到其胞质定位，且与预后不良相关。由于尚无关于肝肿瘤的相关数据，我们对47例连续接受肝细胞癌（HCC）切除术的患者进行了APE1/Ref-1亚细胞定位及其与生存率相关性的研究。通过免疫组织化学法测定HCC及周围肝硬化组织（SLC）中APE1/Ref-1的表达，并与正常肝组织进行比较。使用Kaplan-Meier曲线（对数秩检验）和Cox回归评估生存概率。APE1/Ref-1的胞质表达在HCC中显著高于SLC（P = 0.00001）；正常肝组织仅显示核反应性。低分化HCC患者的胞质表达比高分化HCC患者高3倍（P = 0.03）。胞质定位与中位生存时间短于胞质反应阴性者相关（分别为0.44年和1.64年，P = 0.003），多变量分析证实胞质APE1/Ref-1定位是生存的预测指标。HCC中APE1/Ref-1的胞质表达增加，且与低分化程度和较短生存时间相关，这表明APE1/Ref-1的胞质定位可作为HCC的预后标志物。
