Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis
Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis
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DOI：
10.1371/journal.pone.0143289
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发表时间：
2015-12-01
期刊：
影响因子：
3.7
通讯作者：
Croce, Lory Saveria
中科院分区：
文献类型：
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作者：
Di Maso, Vittorio;Mediavilla, Maria Gabriela;Croce, Lory Saveria
目的人肝细胞癌是世界第五大常见肿瘤，也是慢性肝病(CLD)最严重的并发症。它的发展与慢性炎症和持续的氧化应激有关。无嘌呤脱嘧啶核酸内切酶1/氧化还原效应因子1(APE1/Ref-1)是细胞对氧化应激反应的主要调节因子，它的失控与包括肝细胞癌在内的几种癌症的不良预后有关。体外培养高表达APE1/Ref-1的永生化人肝细胞(IHH)，观察APE1/Ref-1对氧化应激和细胞凋亡的保护作用。APE1/Ref-1mRNA含量随着肝病的进展而增加，其中在肝硬变中的转录上调在肝细胞癌中显着增加。在分化程度较低的癌症中，上调表达更高。在体外，APE1/Ref-1在正常肝细胞中的高表达对氧化应激具有保护作用，并与Bax抑制和逃脱细胞凋亡有关。结论APE1/Ref-1在肝细胞癌中表达上调，与肿瘤的侵袭性有关。这种上调发生在转录水平，它存在于肝癌发生的早期阶段。APE-1/Ref-1过表达与肝细胞存活有关，并抑制Bax活化和细胞凋亡。这些数据提示APE1/Ref-1的过度表达可能在肝细胞存活和肝细胞癌的发生发展中起作用，提示该分子可作为肝癌诊断和治疗的一个有前途的标志物。
ObjectiveHuman 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.DesignIn 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.ResultsAPE1/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.ConclusionAPE1/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.