The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression

Yang,Zhen; Yang,Sun; Misner,Bobbye  J.; Liu-Smith,Feng; Meyskens,Frank  L.

doi:10.3892/ijo.2014.2589

The role of APE/Ref-1 signaling pathway in hepatocellular carcinoma progression

Authors:
- Zhen Yang
- Sun Yang
- Bobbye J. Misner
- Feng Liu-Smith
- Frank L. Meyskens
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Affiliations: Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA
Published online on: August 8, 2014 https://doi.org/10.3892/ijo.2014.2589
Pages: 1820-1828

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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.

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1	Scaggiante B, Kazemi M, Pozzato G, et al: Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol. 20:1268–1288. 2014. View Article : Google Scholar : PubMed/NCBI
2	Bruix J, Boix L, Sala M and Llovet JM: Focus on hepatocellular carcinoma. Cancer Cell. 5:215–219. 2004. View Article : Google Scholar
3	Tien Kuo M and Savaraj N: Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers. Mol Carcinog. 45:701–709. 2006.PubMed/NCBI
4	Tell G, Quadrifoglio F, Tiribelli C and Kelley MR: The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxid Redox Signal. 11:601–620. 2009. View Article : Google Scholar : PubMed/NCBI
5	Bobola MS, Blank A, Berger MS, Stevens BA and Silber JR: Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas. Clin Cancer Res. 7:3510–3518. 2001.PubMed/NCBI
6	Kelley MR, Cheng L, Foster R, et al: Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer. Clin Cancer Res. 7:824–830. 2001.PubMed/NCBI
7	Moore DH, Michael H, Tritt R, Parsons SH and Kelley MR: Alterations in the expression of the DNA repair/redox enzyme APE/ref-1 in epithelial ovarian cancers. Clin Cancer Res. 6:602–609. 2000.PubMed/NCBI
8	Russo D, Arturi F, Bulotta S, et al: ApeI/Ref-I expression and cellular localization in human thyroid carcinoma cell lines. J Endocrinol Invest. 24:10–12. 2001. View Article : Google Scholar : PubMed/NCBI
9	Robertson KA, Bullock HA, Xu Y, et al: Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Res. 61:2220–2225. 2001.PubMed/NCBI
10	Wang D, Luo M and Kelley MR: Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition. Mol Cancer Ther. 3:679–686. 2004.
11	Puglisi F, Aprile G, Minisini AM, et al: Prognostic significance of Ape1/ref-1 subcellular localization in non-small cell lung carcinomas. Anticancer Res. 21:4041–4049. 2001.PubMed/NCBI
12	Kawanishi S, Hiraku Y, Murata M and Oikawa S: The role of metals in site-specific DNA damage with reference to carcinogenesis. Free Radic Biol Med. 32:822–832. 2002.PubMed/NCBI
13	Li Y, Togashi Y, Sato S, et al: Abnormal copper accumulation in non-cancerous and cancerous liver tissues of LEC rats developing hereditary hepatitis and spontaneous hepatoma. Jpn J Cancer Res. 82:490–492. 1991. View Article : Google Scholar : PubMed/NCBI
14	Goodman VL, Brewer GJ and Merajver SD: Copper deficiency as an anti-cancer strategy. Endocr Relat Cancer. 11:255–263. 2004. View Article : Google Scholar : PubMed/NCBI
15	Wu T, Sempos CT, Freudenheim JL, Muti P and Smit E: Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol. 14:195–201. 2004. View Article : Google Scholar : PubMed/NCBI
16	Kuo KW, Chen SF, Wu CC, Chen DR and Lee JH: Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol Trace Elem Res. 89:1–11. 2002. View Article : Google Scholar : PubMed/NCBI
17	Zuo XL, Chen JM, Zhou X, Li XZ and Mei GY: Levels of selenium, zinc, copper and antioxidant enzyme activity in patients with leukemia. Biol Trace Elem Res. 114:41–53. 2006. View Article : Google Scholar : PubMed/NCBI
18	Tashiro H, Kawamoto T, Okubo T and Koide O: Variation in the distribution of trace elements in hepatoma. Biol Trace Elem Res. 95:49–63. 2003. View Article : Google Scholar : PubMed/NCBI
19	Goodman VL, Brewer GJ and Merajver SD: Control of copper status for cancer therapy. Curr Cancer Drug Targets. 5:543–549. 2005. View Article : Google Scholar : PubMed/NCBI
20	Kontoghiorghes GJ, Efstathiou A, Ioannou-Loucaides S and Kolnagou A: Chelators controlling metal metabolism and toxicity pathways: applications in cancer prevention, diagnosis and treatment. Hemoglobin. 32:217–227. 2008. View Article : Google Scholar
21	Harrison L, Ascione AG, Wilson DM III and Demple B: Characterization of the promoter region of the human apurinic endonuclease gene (APE). J Biol Chem. 270:5556–5564. 1995. View Article : Google Scholar : PubMed/NCBI
22	Yang S and Meyskens FL Jr: Alterations in activating protein 1 composition correlate with phenotypic differentiation changes induced by resveratrol in human melanoma. Mol Pharmacol. 67:298–308. 2005. View Article : Google Scholar : PubMed/NCBI
23	Gupte A and Mumper RJ: Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat Rev. 35:32–46. 2009. View Article : Google Scholar : PubMed/NCBI
24	Valko M, Rhodes CJ, Moncol J, Izakovic M and Mazur M: Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 160:1–40. 2006. View Article : Google Scholar : PubMed/NCBI
25	Evans AR, Limp-Foster M and Kelley MR: Going APE over APE/Ref-1. Mutat Res. 461:83–108. 2001. View Article : Google Scholar
26	Merdad A, Karim S, Schulten HJ, et al: Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res. 34:1355–1366. 2014.PubMed/NCBI
27	Ma H, Cai H, Zhang Y, et al: Membrane palmitoylated protein 3 promotes hepatocellular carcinoma cell migration and invasion via up-regulating matrix metalloproteinase 1. Cancer Lett. 344:74–81. 2014. View Article : Google Scholar : PubMed/NCBI
28	Dey S, Ghosh N, Saha D, Kesh K, Gupta A and Swarnakar S: Matrix metalloproteinase-1 (MMP-1) promoter polymorphisms are well linked with lower stomach tumor formation in eastern Indian population. PLoS One. 9:e880402014. View Article : Google Scholar : PubMed/NCBI
29	Teshima J, Doi H, Fujimori K, et al: A human thyroid cancer cell line, DH-14–3, newly established from poorly differentiated thyroid carcinoma. Tohoku J Exp Med. 230:75–82. 2014.PubMed/NCBI
30	Angel P, Baumann I, Stein B, Delius H, Rahmsdorf HJ and Herrlich P: 12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5′-flanking region. Mol Cell Biol. 7:2256–2266. 1987.PubMed/NCBI
31	Gutman A and Wasylyk B: The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J. 9:2241–2246. 1990.PubMed/NCBI
32	Butticè G, Duterque-Coquillaud M, Basuyaux JP, Carrère S, Kurkinen M and Stéhelin D: Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene. 13:2297–2306. 1996.
33	Bendardaf R, Buhmeida A, Ristamäki R, Syrjänen K and Pyrhönen S: MMP-1 (collagenase-1) expression in primary colorectal cancer and its metastases. Scand J Gastroenterol. 42:1473–1478. 2007. View Article : Google Scholar : PubMed/NCBI
34	Miyoshi A, Kitajima Y, Sumi K, et al: Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer. 90:1265–1273. 2004. View Article : Google Scholar : PubMed/NCBI
35	Cano A, Perez-Moreno MA, Rodrigo I, et al: The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2:76–83. 2000. View Article : Google Scholar : PubMed/NCBI
36	Miyoshi A, Kitajima Y, Kido S, et al: Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 92:252–258. 2005.PubMed/NCBI
37	Czabotar PE, Lessene G, Strasser A and Adams JM: Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 15:49–63. 2014. View Article : Google Scholar : PubMed/NCBI
38	Han CR, Jun do Y, Lee JY and Kim YH: Prometaphase arrest-dependent phosphorylation of Bcl-2 and Bim reduces the association of Bcl-2 with Bak or Bim, provoking Bak activation and mitochondrial apoptosis in nocodazole-treated Jurkat T cells. Apoptosis. 19:224–240. 2014. View Article : Google Scholar : PubMed/NCBI
39	Cao W, Zhang JL, Feng DY, et al: The effect of adenovirus-conjugated NDRG2 on p53-mediated apoptosis of hepatocarcinoma cells through attenuation of nucleotide excision repair capacity. Biomaterials. 35:993–1003. 2014. View Article : Google Scholar : PubMed/NCBI
40	Yang CF, Peng LX, Huang TJ, et al: Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway. Cancer Lett. 344:260–271. 2014. View Article : Google Scholar