The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression.
The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression.
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APE/Ref-1信号通路在肝细胞癌进展中的作用。
DOI：
10.3892/ijo.2014.2589
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发表时间：
2014-11
影响因子：
5.2
通讯作者：
Meyskens FL
中科院分区：
文献类型：
--
作者：
Yang Z;Yang S;Misner BJ;Liu-Smith F;Meyskens FL
肝细胞癌（HCC）占全球估计癌症死亡人数的三分之一。深入了解控制肝癌进展的机制对于开发新的治疗方法至关重要。已发现脱嘌呤/脱嘧啶核酸内切酶-1/氧化还原效应因子1（APE/Ref-1）在各种类型的癌症（包括HCC）中升高。此外，HCC进展总是与铜（Cu）升高相关。我们以前的数据表明，铜处理启动APE/Ref-1表达及其下游靶点。因此，我们推测APE/Ref-1可能通过介导Cu对其信号级联的影响而参与HCC的进展。在不同的处理后，分析人肝癌细胞系（Hep 3B）和永生化非恶性肝细胞系（THLE 3），以探讨APE/Ref-1信号通路的作用。采用免疫组化方法检测APE/Ref-1蛋白表达与临床特征的关系。APE/Ref-1在HCC细胞中上调，这与APE/Ref-1在HCC组织芯片中的强表达一致。APE/Ref-1在低分化和更具侵袭性的肿瘤中的细胞质积聚更大。我们还提供了证据表明APE/Ref-1信号通路刺激细胞增殖，增强抗凋亡，并通过在Hep 3B细胞中使用siRNA或在THLE 3细胞中过表达APE/Ref-1的实验性敲低APE/Ref-1来促进转移。这些结果确定了APE/Ref-1作为重要的介导和增强分子在HCC进展中的新作用，并且还为进一步研究利用适当的APE/Ref-1抑制剂与化学药物组合用于HCC治疗提供了基础。
Hepatocellular carcinoma (HCC) is responsible for a third of the estimated cancer-caused deaths worldwide. To deeply understand the mechanisms controlling HCC progression is of primary importance to develop new approaches for treatment. Apurinic/apyrimidinic endonuclease-1/redox effector factor 1 (APE/Ref-1) has been uncovered elevated in various types of cancer, including HCC. Additionally, HCC progression is always correlated with elevated copper (Cu). Our previous data demonstrated that Cu treatment initiated APE/Ref-1 expression and its downstream targets. Therefore, we hypothesized that APE/Ref-1 may be involved in HCC progression through mediating the effect of Cu to its signaling cascades. Following different treatments, human HCC cell line (Hep3B) and immortalized non-malignant hepatocyte cell line (THLE3) were analyzed to explore the role of APE/Ref-1 signaling pathway. Unstained human tissue microarrays (TMA) were subjected to IHC analysis to study the relationship between APE/Ref-1 expression and clinic features. APE/Ref-1 was upregulated in HCC cells consistent with the strong expression of APE/Ref-1 in HCC tissue microarray. Greater cytoplasmic accumulation of APE/Ref-1 was found in poorly differentiated and more aggressive tumors. Also we provide evidence to show that APE/Ref-1 signaling pathway stimulates cellular proliferation, enhances antiapoptosis, and facilitates metastasis through experimental knockdown of APE/Ref-1 using siRNA in Hep3B cells or overexpressing APE/Ref-1 in THLE3 cells. These results define a novel role of APE/Ref-1 in HCC progression as being an important mediating and potentiating molecule, and also provide a basis for further investigations utilizing appropriate APE/Ref-1 inhibitors in combination with chemo-drugs for HCC treatment.