TNFAIP3 overexpression is an independent factor for poor survival in esophageal squamous cell carcinoma

Hadisaputri,Yuni  Elsa; Miyazaki,Tatsuya; Yokobori,Takehiko; Sohda,Makoto; Sakai,Makoto; Ozawa,Daigo; Hara,Keigo; Honjo,Hiroaki; Kumakura,Yuji; Kuwano,Hiroyuki

doi:10.3892/ijo.2017.3869

TNFAIP3 overexpression is an independent factor for poor survival in esophageal squamous cell carcinoma

Authors:
- Yuni Elsa Hadisaputri
- Tatsuya Miyazaki
- Takehiko Yokobori
- Makoto Sohda
- Makoto Sakai
- Daigo Ozawa
- Keigo Hara
- Hiroaki Honjo
- Yuji Kumakura
- Hiroyuki Kuwano
View Affiliations

Affiliations: Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan, Department of Molecular and Cellular Pharmacology, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Published online on: February 9, 2017 https://doi.org/10.3892/ijo.2017.3869
Pages: 1002-1010

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tumor necrosis factor α induced protein 3 (TNFAIP3) is a protein that is induced by TNF-mediated NF-κB activation and has a dual function in regulating NF-κB. TNFAIP3 is associated with inflammatory carcinogenesis in many cancer types. However, the clinical significance of TNFAIP3 expression and function in esophageal squamous cell carcinoma (ESCC) has not yet been reported. We examined 149 ESCC tissue specimens to determine the clinical significance of TNFAIP3 by immunohistochemistry. Western blot analyses were used to detect TNFAIP3 expression in TE-1, TE-8, TE-15 and KYSE-70 ESCC cells and in Het-1A, a non-cancerous esophageal cell line. TNFAIP3 protein knockdown was conducted using small-interfering RNA to investigate its impact on cell proliferation, migration and invasion. Significant correlations between TNFAIP3 expression and differentiation (P=0.04) among clinicopathological characteristics of ESCC patients were demonstrated, and high TNFAIP3 expression was associated with poor survival (P=0.02). Moreover, multivariate analysis result showed that high TNFAIP3 expression was an independent factor for poor survival (P=0.04). In vitro analysis showed high expression of TNFAIP3 protein in TE-15 cells and low expression in Het-1A cells. Furthermore, the proliferation, migration and invasion of TE-15 cells after TNFAIP3 suppression by siRNA were significantly reduced. These findings suggest that TNFAIP3 protein may be an independent prognostic marker for poor survival, and a promising target for ESCC therapy.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
2	Arnold M, Soerjomataram I, Ferlay J and Forman D: Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 64:381–387. 2015. View Article : Google Scholar
3	Pennathur A, Gibson MK, Jobe BA and Luketich JD: Oesophageal carcinoma. Lancet. 381:400–412. 2013. View Article : Google Scholar : PubMed/NCBI
4	Napier KJ, Scheerer M and Misra S: Esophageal cancer: A review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 6:112–120. 2014. View Article : Google Scholar : PubMed/NCBI
5	Dixit VM, Green S, Sarma V, Holzman LB, Wolf FW, O'Rourke K, Ward PA, Prochownik EV and Marks RM: Tumor necrosis factor-α induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem. 265:2973–2978. 1990.PubMed/NCBI
6	Opipari AW Jr, Boguski MS and Dixit VM: The A20 cDNA induced by tumor necrosis factor α encodes a novel type of zinc finger protein. J Biol Chem. 265:14705–14708. 1990.PubMed/NCBI
7	Krikos A, Laherty CD and Dixit VM: Transcriptional activation of the tumor necrosis factor α-inducible zinc finger protein, A20, is mediated by kappa B elements. J Biol Chem. 267:17971–17976. 1992.PubMed/NCBI
8	Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, et al: De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 430:694–699. 2004. View Article : Google Scholar : PubMed/NCBI
9	Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, Phu L, Phung Q, Maurer B, Arnott D, et al: Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling. Mol Cell. 40:548–557. 2010. View Article : Google Scholar : PubMed/NCBI
10	Opipari AW Jr, Hu HM, Yabkowitz R and Dixit VM: The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. J Biol Chem. 267:12424–12427. 1992.PubMed/NCBI
11	Song HY, Rothe M and Goeddel DV: The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci USA. 93:6721–6725. 1996. View Article : Google Scholar : PubMed/NCBI
12	Heyninck K, De Valck D, Vanden Berghe W, Van Criekinge W, Contreras R, Fiers W, Haegeman G and Beyaert R: The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. J Cell Biol. 145:1471–1482. 1999. View Article : Google Scholar : PubMed/NCBI
13	Zhang SQ, Kovalenko A, Cantarella G and Wallach D: Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity. 12:301–311. 2000. View Article : Google Scholar
14	Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP and Ma A: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 289:2350–2354. 2000. View Article : Google Scholar : PubMed/NCBI
15	De Valck D, Jin DY, Heyninck K, Van de Craen M, Contreras R, Fiers W, Jeang KT and Beyaert R: The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases. Oncogene. 18:4182–4190. 1999. View Article : Google Scholar : PubMed/NCBI
16	Ma A and Malynn BA: A20: Linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol. 12:774–785. 2012. View Article : Google Scholar : PubMed/NCBI
17	Hadisaputri YE, Miyazaki T, Suzuki S, Yokobori T, Kobayashi T, Tanaka N, Inose T, Sohda M and Kuwano H: TNFAIP8 overexpression: Clinical relevance to esophageal squamous cell carcinoma. Ann Surg Oncol. 19(Suppl 3): S589–S596. 2012. View Article : Google Scholar
18	Wang MC, Liu SX and Liu PB: Gene expression profile of multiple myeloma cell line treated by realgar. J Exp Clin Cancer Res. 25:243–249. 2006.PubMed/NCBI
19	Vendrell JA, Ghayad S, Ben-Larbi S, Dumontet C, Mechti N and Cohen PA: A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells. Oncogene. 26:4656–4667. 2007. View Article : Google Scholar : PubMed/NCBI
20	Wang Q, Yuan L, Liu Z, Yin J, Jiang X and Lu J: Expression of A20 is reduced in pancreatic cancer tissues. J Mol Histol. 43:319–325. 2012. View Article : Google Scholar : PubMed/NCBI
21	Dong B, Lv G, Wang Q, Wei F, Bellail AC, Hao C and Wang G: Targeting A20 enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 418:433–438. 2012. View Article : Google Scholar : PubMed/NCBI
22	Wang M and Li S: Bladder polypoid cystitis-derived A20 associates with tumorigenesis. Cell Biochem Biophys. 67:669–673. 2013. View Article : Google Scholar : PubMed/NCBI
23	Ghadban T, Schmidt-Yang M, Uzunoglu FG, Perez DR, Tsui TY, El gammal AT, Erbes PJ, Zilbermints V, Wellner U, Pantel K, et al: An A/C germline single-nucleotide polymorphism in the TNFAIP3 gene is associated with advanced disease stage and survival in only surgically treated esophageal cancer. J Hum Genet. 59:661–666. 2014. View Article : Google Scholar : PubMed/NCBI
24	Lademann U, Kallunki T and Jäättelä M: A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins. Cell Death Differ. 8:265–272. 2001. View Article : Google Scholar : PubMed/NCBI
25	Daniel S, Arvelo MB, Patel VI, Longo CR, Shrikhande G, Shukri T, Mahiou J, Sun DW, Mottley C, Grey ST, et al: A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood. 104:2376–2384. 2004. View Article : Google Scholar : PubMed/NCBI
26	Hjelmeland AB, Wu Q, Wickman S, Eyler C, Heddleston J, Shi Q, Lathia JD, Macswords J, Lee J, McLendon RE, et al: Targeting A20 decreases glioma stem cell survival and tumor growth. PLoS Biol. 8:e10003192010. View Article : Google Scholar : PubMed/NCBI
27	Sun X, Chen E, Dong R, Chen W and Hu Y: Nuclear factor (NF)-κB p65 regulates differentiation of human and mouse lung fibroblasts mediated by TgF-β. Life Sci. 122:8–14. 2015. View Article : Google Scholar
28	Murtas D, Maric D, De Giorgi V, Reinboth J, Worschech A, Fetsch P, Filie A, Ascierto ML, Bedognetti D, Liu Q, et al: IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes. Br J Cancer. 109:76–82. 2013. View Article : Google Scholar : PubMed/NCBI
29	Codd JD, Salisbury JR, Packham G and Nicholson LJ: A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma. J Pathol. 187:549–555. 1999. View Article : Google Scholar : PubMed/NCBI
30	da Silva CG, Studer P, Skroch M, Mahiou J, Minussi DC, Peterson CR, Wilson SW, Patel VI, Ma A, Csizmadia E, et al: A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology. 57:2014–2025. 2013. View Article : Google Scholar :
31	Murphy SF, Rhee L, Grimm WA, Weber CR, Messer JS, Lodolce JP, Chang JE, Bartulis SJ, Nero T, Kukla RA, et al: Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice. Am J Physiol Gastrointest Liver Physiol. 307:G871–G882. 2014. View Article : Google Scholar : PubMed/NCBI
32	Moll HP, Lee A, Minussi DC, da Silva CG, Csizmadia E, Bhasin M and Ferran C: A20 regulates atherogenic interferon (IFN)-γ signaling in vascular cells by modulating basal IFNβ levels. J Biol Chem. 289:30912–30924. 2014. View Article : Google Scholar : PubMed/NCBI