Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most aggressive neoplasms, and is responsible for a third of the estimated cancer-caused deaths worldwide [1]
Cu treatment led to the translocation of APE/Ref-1 quantified by the ratio of cytoplasmic/nuclear relative density values (Fig. 4E)
Enhanced cytoplasmic accumulation of APE/Ref-1 was accompanied with an upregulation of matrix metalloproteinase-1 (MMP-1) and Snail and a downregulation of E-cadherin, proposing that Cu and APE/Ref-1 cytoplasmic distribution might be associated with HCC development
Summary
Hepatocellular carcinoma (HCC) is one of the most aggressive neoplasms, and is responsible for a third of the estimated cancer-caused deaths worldwide [1]. A deeper understanding of the mechanisms controlling HCC progression is of primary importance to develop new approaches for treatment [2,3]. Emerging evidence indicates that APE/Ref-1 has been uncovered elevated in various types of cancer, and its subcellular distribution is closely correlated with tumor aggressiveness, resistance to radiotherapy, and poor outcome [5,6,7,8,9,10,11]. APE/Ref-1 is unregulated in HCC cells and in liver cancer tissue microarray; the functional role of APE/Ref-1 in tumor pathogenesis and progression is not yet clear
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