title: The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression.
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 anti-apoptosis, 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.
authors.affiliation: Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Sun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Bobbye J
authors.initials: BJ
authors.lastname: Misner
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu-Smith
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Meyskens
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000008:administration & dosage; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; D003300:Copper
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