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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression

Authors: Haiyang Chen, Liang Hu, Zaili Luo, Jian Zhang, Cunzhen Zhang, Bijun Qiu, Liwei Dong, Yexiong Tan, Jin Ding, Shanhua Tang, Feng Shen, Zhong Li, Hongyang Wang

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

Aberrant expression of A20 has been reported in several human malignancies including hepatocellular carcinoma (HCC). However, its clinical relevance and potential role in HCC remain unknown.

Methods

Quantitative PCR, Western blots and immunohistochemistry analyses were used to quantify A20 expression in HCC samples and cell lines. The correlation of A20 expression with clinicopathologic features was analyzed in a cohort containing 143 patients with primary HCC. Kaplan-Meier curves were used to evaluate the association between A20 expression and patient survival. Functional studies were performed to determine the effects of A20 on proliferation and metastasis of HCC cells in vitro and in vivo.

Results

Expression of A20 was increased in HCC tissues and cell lines. Increased expression of A20 was negatively correlated with the tumor size, TNM stage, tumor thrombus formation, capsular invasion and serum AFP levels. Patients with higher A20 expression had a prolonged disease-free survival and overall survival than those with lower A20 expression. Forced expression of A20 significantly inhibited the proliferative and invasive properties of HCC cells both in vitro and in vivo, whereas knockdown of A20 expression showed the opposite effects. Further studies revealed that expression of A20 was inversely correlated with Twist1 levels and NF-κB activity in HCC tissues and cell lines. A20-induced suppression of proliferation and migration of HCC cells were mainly mediated through inhibition of Twist1 expression that was regulated at least partly by A20-induced attenuation of NF-κB activity.

Conclusions

Our results demonstrate that A20 plays a negative role in the development and progression of HCC probably through inhibiting Twist1 expression. A20 may serve as a novel prognostic biomarker and potential therapeutic target for HCC patients.
Appendix
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Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed
2.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38.CrossRefPubMed
3.
4.
Dixit VM, Green S, Sarma V, Holzman LB, Wolf FW, O'Rourke K, et al. Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem. 1990;265(5):2973–8.PubMed
5.
Hymowitz SG, Wertz IE. A20: from ubiquitin editing to tumour suppression. Nat Rev Cancer. 2010;10(5):332–41.CrossRefPubMed
6.
Ando M, Sato Y, Takata K, Nomoto J, Nakamura S, Ohshima K, et al. A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas. PLoS One. 2013;8(2):e56741.PubMedCentralCrossRefPubMed
7.
Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459(7247):712–6.CrossRefPubMed
8.
Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura S, Morishima Y, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood. 2009;114(12):2467–75.CrossRefPubMed
9.
Braun FC, Grabarczyk P, Mobs M, Braun FK, Eberle J, Beyer M, et al. Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sezary syndrome. Leukemia. 2011;25(9):1494–501.CrossRefPubMed
10.
Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med. 2009;206(5):981–9.PubMedCentralCrossRefPubMed
11.
Wang Q, Yuan L, Liu Z, Yin J, Jiang X, Lu J. Expression of A20 is reduced in pancreatic cancer tissues. J Mol Histol. 2012;43(3):319–25.CrossRefPubMed
12.
Bellail AC, Olson JJ, Yang X, Chen ZJ, Hao C. A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov. 2012;2(2):140–55.PubMedCentralCrossRefPubMed
13.
Hjelmeland AB, Wu Q, Wickman S, Eyler C, Heddleston J, Shi Q, et al. Targeting A20 decreases glioma stem cell survival and tumor growth. PLoS Biol. 2010;8(2):e1000319.PubMedCentralCrossRefPubMed
14.
Wang M, Li S. Bladder polypoid cystitis-derived A20 associates with tumorigenesis. Cell Biochem Biophys. 2013;67(2):669–73.CrossRefPubMed
15.
Guo Q, Dong H, Liu X, Wang C, Liu N, Zhang J, et al. A20 is overexpressed in glioma cells and may serve as a potential therapeutic target. Expert Opin Ther Targets. 2009;13(7):733–41.CrossRefPubMed
16.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMed
17.
da Silva CG, Cervantes JR, Studer P, Ferran C. A20--an omnipotent protein in the liver: prometheus myth resolved? Adv Exp Med Biol. 2014;809:117–39.CrossRefPubMed
18.
Dong B, Lv G, Wang Q, Wei F, Bellail AC, Hao C, et al. Targeting A20 enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2012;418(2):433–8.CrossRefPubMed
19.
Li Y, Tang Y, Ye L, Liu B, Liu K, Chen J, et al. Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol. 2003;129(1):43–51.PubMed
20.
Wang RY, Chen L, Chen HY, Hu L, Li L, Sun HY, et al. MUC15 inhibits dimerization of EGFR and PI3K-AKT signaling and is associated with aggressive hepatocellular carcinomas in patients. Gastroenterology. 2013;145(6):1436–48. e1431-1412.CrossRefPubMed
21.
Tang L, Tan YX, Jiang BG, Pan YF, Li SX, Yang GZ, et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin Cancer Res. 2013;19(8):2014–24.CrossRefPubMed
22.
Li W, Yu CP, Xia JT, Zhang L, Weng GX, Zheng HQ, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 2009;15(4):1393–9.CrossRefPubMed
23.
Hu L, Chen HY, Cai J, Zhang Y, Qi CY, Gong H, et al. Serine threonine tyrosine kinase 1 is a potential prognostic marker in colorectal cancer. BMC Cancer. 2015;15(1):246.PubMedCentralCrossRefPubMed
24.
Hu L, Chen L, Yang G, Li L, Sun H, Chang Y, et al. HBx sensitizes cells to oxidative stress-induced apoptosis by accelerating the loss of Mcl-1 protein via caspase-3 cascade. Mol Cancer. 2011;10:43.PubMedCentralCrossRefPubMed
25.
Fu J, Chen Y, Cao J, Luo T, Qian YW, Yang W, et al. p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1alpha pathways. Hepatology. 2011;53(1):181–92.CrossRefPubMed
26.
Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science. 2010;327(5969):1135–9.PubMedCentralCrossRefPubMed
27.
Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, et al. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012;72(5):1290–300.PubMedCentralCrossRefPubMed
28.
Pham CG, Bubici C, Zazzeroni F, Knabb JR, Papa S, Kuntzen C, et al. Upregulation of Twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs. Mol Cell Biol. 2007;27(11):3920–35.PubMedCentralCrossRefPubMed
29.
Kumar M, Allison DF, Baranova NN, Wamsley JJ, Katz AJ, Bekiranov S, et al. NF-kappaB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells. PLoS One. 2013;8(7):e68597.PubMedCentralCrossRefPubMed
30.
Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.CrossRefPubMed
31.
32.
33.
34.
Luedde T, Schwabe RF. NF-kappaB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(2):108–18.PubMedCentralCrossRefPubMed
35.
Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, et al. Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20. J Mol Biol. 2008;376(2):526–40.PubMedCentralCrossRefPubMed
36.
Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430(7000):694–9.CrossRefPubMed
37.
Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004;5(10):1052–60.CrossRefPubMed
38.
Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival. Ann Surg. 2007;245(1):51–8.PubMedCentralCrossRefPubMed
39.
Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009;459(7247):717–21.PubMedCentralCrossRefPubMed
40.
Longo CR, Patel VI, Shrikhande GV, Scali ST, Csizmadia E, Daniel S, et al. A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism. Hepatology. 2005;42(1):156–64.CrossRefPubMed
41.
da Silva CG, Studer P, Skroch M, Mahiou J, Minussi DC, Peterson CR, et al. A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology. 2013;57(5):2014–25.PubMedCentralCrossRefPubMed
42.
Lerebours F, Vacher S, Andrieu C, Espie M, Marty M, Lidereau R, et al. NF-kappa B genes have a major role in inflammatory breast cancer. BMC Cancer. 2008;8:41.PubMedCentralCrossRefPubMed
43.
Codd JD, Salisbury JR, Packham G, Nicholson LJ. A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma. J Pathol. 1999;187(5):549–55.CrossRefPubMed
44.
Khan MA, Chen HC, Zhang D, Fu J. Twist: a molecular target in cancer therapeutics. Tumour Biol. 2013;34(5):2497–506.CrossRefPubMed
45.
Qin Q, Xu Y, He T, Qin C, Xu J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 2012;22(1):90–106.PubMedCentralCrossRefPubMed
46.
Luo GQ, Li JH, Cao L, Zhou YH, Wen JF. Activator protein-1 involvement in proliferation inhibition by gene silencing of Twist in gastric cancer cells. Pathology. 2011;43(7):697–701.CrossRefPubMed
47.
48.
Qiang L, Zhao B, Ming M, Wang N, He TC, Hwang S, et al. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc Natl Acad Sci U S A. 2014;111(25):9241–6.PubMedCentralCrossRefPubMed
49.
Okamura H, Yoshida K, Haneji T. Negative regulation of TIMP1 is mediated by transcription factor TWIST1. Int J Oncol. 2009;35(1):181–6.PubMed
50.
Weiss MB, Abel EV, Mayberry MM, Basile KJ, Berger AC, Aplin AE. TWIST1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells. Cancer Res. 2012;72(24):6382–92.PubMedCentralCrossRefPubMed
51.
Zhao XL, Sun T, Che N, Sun D, Zhao N, Dong XY, et al. Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1. J Cell Mol Med. 2011;15(3):691–700.PubMedCentralCrossRefPubMed
52.
Terauchi M, Kajiyama H, Yamashita M, Kato M, Tsukamoto H, Umezu T, et al. Possible involvement of TWIST in enhanced peritoneal metastasis of epithelial ovarian carcinoma. Clin Exp Metastasis. 2007;24(5):329–39.CrossRefPubMed
Metadata
Title
A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression
Authors
Haiyang Chen
Liang Hu
Zaili Luo
Jian Zhang
Cunzhen Zhang
Bijun Qiu
Liwei Dong
Yexiong Tan
Jin Ding
Shanhua Tang
Feng Shen
Zhong Li
Hongyang Wang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0454-6

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