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Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary research

Human basonuclin 2 up-regulates a cascade set of interferon-stimulated genes with anti-cancerous properties in a lung cancer model

Authors: Egon Urgard, Anu Reigo, Eva Reinmaa, Ana Rebane, Andres Metspalu

Published in: Cancer Cell International | Issue 1/2017

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Abstract

Background

Human basonuclin 2 (BNC2) acts as a tumor suppressor in multiple cancers in an as yet unidentified manner. The role and expression of the BNC2 gene in lung cancer has not yet been investigated.

Methods

BNC2 expression was studied in the A549 and BEAS-2B cell lines, as well as in lung cancer tissue. Illumina array analysis and a viability assay were used to study the effects of transient transfection of BNC2 in A549 cells. Ingenuity pathway analysis and g:Profiler were applied to identify affected pathways and networks. RT-qPCR was used to validate the array results.

Results

We showed the reduced mRNA expression of BNC2 in non-small cell lung cancer tissue and lung cancer cell line A549 compared to non-cancerous lung tissue and BEAS-2B cells, respectively. Further array analysis demonstrated that the transfection of BNC2 into A549 cells resulted in the increased expression of 139 genes and the down-regulation of 13 genes. Pathway analysis revealed that half of the up-regulated genes were from the interferon/signal transducer and activator of transcription signaling pathways. The differential expression of selected sets of genes, including interferon-stimulated and tumor suppressor genes of the XAF1 and OAS families, was confirmed by RT-qPCR. In addition, we showed that the over-expression of BNC2 inhibited the proliferation of A549 cells.

Conclusion

Our data suggest that human BNC2 is an activator of a subset of IFN-regulated genes and might thereby act as a tumor suppressor.
Appendix
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Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN. Int J Cancer. 2012;136:E359–86.CrossRef
2.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2012;49:1374–403.CrossRef
3.
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2015. Ca-a Cancer J Clinicians. 2015;65:5–29.CrossRef
4.
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, et al. Cancer treatment and survivorship statistics. CA Cancer J Clin. 2012;62:220–41.CrossRefPubMed
5.
Chae YK, Pan A, Davis AA, Raparia K, Mohindra NA, Matsangou M, Giles FJ. Biomarkers for PD-1/PD-L1 blockade therapy in non-small-cell lung cancer: is PD-L1 expression a good marker for patient selection? Clin Lung Cancer. 2016;17:350–61.CrossRefPubMed
6.
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837–46.CrossRefPubMed
7.
8.
Wilderman MJ, Sun J, Jassar AS, Kapoor V, Khan M, Vachani A, Suzuki E, Kinniry PA, Sterman DH, Kaiser LR, Albelda SM. Intrapulmonary IFN-beta gene therapy using an adenoviral vector is highly effective in a murine orthotopic model of bronchogenic adenocarcinoma of the lung. Cancer Res. 2005;65:8379–87.CrossRefPubMed
9.
Antoniou KM, Ferdoutsis E, Bouros D. Interferons and their application in the diseases of the lung. Chest. 2003;123:209–16.CrossRefPubMed
10.
Chua PK, McCown MF, Rajyaguru S, Kular S, Varma R, Symons J, Chiu SS, Cammack N, Najera I. Modulation of alpha interferon anti-hepatitis C virus activity by ISG15. J Gen Virol. 2009;90:2929–39.CrossRefPubMed
11.
12.
Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–55.CrossRefPubMed
13.
Taniguchi T, Takaoka A. The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr Opin Immunol. 2002;14:111–6.CrossRefPubMed
14.
Khodarev NN, Roizman B, Weichselbaum RR. Molecular pathways: interferon/Stat1 pathway: role in the tumor resistance to genotoxic stress and aggressive growth. Clin Cancer Res. 2012;18:3015–21.CrossRefPubMed
15.
Itsui Y, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Koyama T, Takeda Y, Nakagawa M, Kakinuma S, Sekine Y, et al. Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J Viral Hepatitis. 2006;13:690–700.CrossRef
16.
Leaman DW, Chawla-Sarkar M, Jacobs B, Vyas K, Sun YP, Ozdemir A, Yi TL, Williams BR, Borden EC. Novel growth and death related interferon-stimulated genes (ISGs) in melanoma: greater potency of IFN-beta compared with IFN-alpha 2. J Interferon Cytokine Res. 2003;23:745–56.CrossRefPubMed
17.
Der SD, Zhou AM, Williams BRG, Silverman RH. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA. 1998;95:15623–8.CrossRefPubMedPubMedCentral
18.
de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BRG. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69:912–20.PubMed
19.
Romano RA, Li H, Tummala R, Maul R, Sinha S. Identification of basonuclin2, a DNA-binding zinc-finger protein expressed in germ tissues and skin keratinocytes. Genomics. 2004;83:821–33.CrossRefPubMed
20.
Vanhoutteghem A, Djian P. Basonuclin 2: an extremely conserved homolog of the zinc finger protein basonuclin. Proc Natl Acad Sci USA. 2004;101:3468–73.CrossRefPubMedPubMedCentral
21.
Vanhoutteghem A, Djian P. Basonuclins 1 and 2, whose genes share a common origin, are proteins with widely different properties and functions. Proc Natl Acad Sci USA. 2006;103:12423–8.CrossRefPubMedPubMedCentral
22.
Bhoj EJ, Ramos P, Baker LA, Garg V, Cost N, Nordenskjold A, Elder FF, Bleyl SB, Bowles NE, Arrington CB, et al. Human balanced translocation and mouse gene inactivation implicate basonuclin 2 in distal urethral development. Eur J Hum Genet. 2011;19:540–6.CrossRefPubMedPubMedCentral
23.
Jacobs LC, Hamer MA, Gunn DA, Deelen J, Lall JS, van Heemst D, Uh HW, Hofman A, Uitterlinden AG, Griffiths CE, et al. A Genome-wide association study identifies the skin color genes IRF4, MC1R, ASIP, and BNC2 influencing facial pigmented spots. J Invest Dermatol. 2015;135:1735–42.CrossRefPubMed
24.
Asgari MM, Wang W, Ioannidis NM, Itnyre J, Hoffmann T, Jorgenson E, Whittemore AS. Identification of susceptibility loci for cutaneous squamous cell carcinoma. J Invest Dermatol. 136:930–37.
25.
Chahal HS, Lin Y, Ransohoff KJ, Hinds DA, Wu W, Dai HJ, Qureshi AA, Li WQ, Kraft P, Tang JY, et al. Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nat Commun. 2016;7:12048.CrossRefPubMedPubMedCentral
26.
Goode EL, Chenevix-Trench G, Song H, Ramus SJ, Notaridou M, Lawrenson K, Widschwendter M, Vierkant RA, Larson MC, Kjaer SK, et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet. 2010;42:874–9.CrossRefPubMedPubMedCentral
27.
Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A, Wozniak E, Anton-Culver H, Chang-Claude J, Cramer DW, DiCioccio R, et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet. 2009;41:996–1000.CrossRefPubMedPubMedCentral
28.
Winham SJ, Armasu SM, Cicek MS, Larson MC, Cunningham JM, Kalli KR, Fridley BL, Goode EL. Genome-wide investigation of regional blood-based DNA methylation adjusted for complete blood counts implicates BNC2 in ovarian cancer. Genet Epidemiol. 2014;38:457–66.CrossRefPubMedPubMedCentral
29.
Huang CN, Huang SP, Pao JB, Chang TY, Lan YH, Lu TL, Lee HZ, Juang SH, Wu PP, Pu YS, et al. Genetic polymorphisms in androgen receptor-binding sites predict survival in prostate cancer patients receiving androgen-deprivation therapy. Ann Oncol. 2011;23:707–13.CrossRefPubMed
30.
Sun Y, Jia X, Hou L, Liu X. Screening of differently expressed miRNA and mRNA in prostate cancer by integrated analysis of transcription data. Urology. 2019;94:313.
31.
Akagi T, Ito T, Kato M, Jin Z, Cheng Y, Kan T, Yamamoto G, Olaru A, Kawamata N, Boult J, et al. Chromosomal abnormalities and novel disease-related regions in progression from Barrett’s esophagus to esophageal adenocarcinoma. Int J Cancer. 2009;125:2349–59.CrossRefPubMedPubMedCentral
32.
Wu Y, Zhang X, Liu Y, Lu F, Chen X. Decreased expression of BNC1 and BNC2 is associated with genetic or epigenetic regulation in hepatocellular carcinoma. Int J Mol Sci. 2016;17:153.CrossRefPubMedCentral
33.
Cesaratto L, Grisard E, Coan M, ZandonĆ L, De Mattia E, Poletto E, Cecchin E, Puglisi F, Canzonieri V, Mucignat MT, et al. BNC2 is a putative tumor suppressor gene in high-grade serous ovarian carcinoma and impacts cell survival after oxidative stress. Cell Death Dis. 2016;7:e2374.CrossRefPubMedPubMedCentral
34.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.CrossRefPubMed
35.
Saviozzi S, Cordero F, Iacono M, Novello S, Giorgio S, Calogero R. Selection of suitable reference genes for accurate normalization of gene expression profile studies in non-small cell lung cancer. BMC Cancer. 2000;6:200.CrossRef
36.
Du P, Kibbe WA, Lin SM. Lumi: a pipeline for processing Illumina microarray. Bioinformatics. 2008;24:1547–8.CrossRefPubMed
37.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRefPubMedPubMedCentral
38.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc: Ser B (Methodol). 1995;57:289–300.
39.
Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, Vilo J. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 2016;44:W83–9.CrossRefPubMedPubMedCentral
40.
Xiang Y, Wang Z, Murakami J, Plummer S, Klein EA, Carpten JD, Trent JM, Isaacs WB, Casey G, Silverman RH. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2′,5′-oligoadenylates. Cancer Res. 2003;63:6795–801.PubMed
41.
Malathi K, Paranjape JM, Ganapathi R, Silverman RH. HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2′,5′-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2004;64:9144–51.CrossRefPubMed
42.
Zhu LM, Shi DM, Dai Q, Cheng XJ, Yao WY, Sun PH, Ding Y, Qiao MM, Wu YL, Jiang SH, Tu SP. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma. Oncotarget. 2014;5:5403–15.CrossRefPubMedPubMedCentral
43.
Andrews HN, Mullan PB, McWilliams S, Sebelova S, Quinn JE, Gilmore PM, McCabe N, Pace A, Koller B, Johnston PG, et al. BRCA1 regulates the interferon gamma-mediated apoptotic response. J Biol Chem. 2002;277:26225–32.CrossRefPubMed
44.
Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol. 2001;3:128–33.CrossRefPubMed
45.
Maia CJ, Rocha SM, Socorro S, Schmitt F, Santos CR. Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones. 2016; 2.
46.
Nagahata T, Sato T, Tomura A, Onda M, Nishikawa K, Emi M. Identification of RAI3 as a therapeutic target for breast cancer. Endocr Relat Cancer. 2005;12:65–73.CrossRefPubMed
47.
Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG. Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics. 2000;70:113–22.CrossRefPubMed
48.
Bunn PA. Worldwide overview of the current status of lung cancer diagnosis and treatment. Arch Pathol Lab Med. 2012;136:1478–81.CrossRefPubMed
49.
Vanhoutteghem A, Maciejewski-Duval A, Bouche C, Delhomme B, Herve F, Daubigney F, Soubigou G, Araki M, Araki K, Yamamura K, Djian P. Basonuclin 2 has a function in the multiplication of embryonic craniofacial mesenchymal cells and is orthologous to disco proteins. Proc Natl Acad Sci USA. 2009;106:14432–7.CrossRefPubMedPubMedCentral
50.
Sanchez-Palencia A, Gomez-Morales M, Gomez-Capilla JA, Pedraza V, Boyero L, Rosell R, Farez-Vidal ME. Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer. Int J Cancer. 2011;129:355–64.CrossRefPubMed
51.
Einav U, Tabach Y, Getz G, Yitzhaky A, Ozbek U, Amariglio N, Izraeli S, Rechavi G, Domany E. Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer. Oncogene. 2005;24:6367–75.PubMed
52.
Mengual L, Ars E, Lozano JJ, Burset M, Izquierdo L, Ingelmo M, Gaya JM, Algaba F, Villavicencio H, Ribal MJ, Alcaraz A. Gene expression profiles in prostate cancer identification of candidate non-invasive diagnostic markers. Actas UrolĆ3gicas EspaĆ ± olas (English Edition). 2014;38:143–9.CrossRef
53.
Long J, Liu Z, Wu X, Xu Y, Ge C. Gene expression profile analysis of pancreatic cancer based on microarray data. Mol Med Rep. 2016;13:3919.
54.
Chepovetsky J, Kalir T, Weiderpass E. Clinical applicability of microarray technology in the diagnosis, prognostic stratification, treatment and clinical surveillance of cervical adenocarcinoma. Curr Pharm Des. 2013;19:1425–9.PubMed
55.
Tseng GC, Cheng C, Yu YP, Nelson J, Michalopoulos G, Luo JH. Investigating multi-cancer biomarkers and their cross-predictability in the expression profiles of multiple cancer types. Biomark Insights. 2009;4:57–79.PubMedPubMedCentral
56.
57.
Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119:3573–85.PubMedPubMedCentral
58.
Li S, Wang L, Berman M, Kong YY, Dorf ME. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity. 2011;35:426–40.CrossRefPubMedPubMedCentral
59.
Rosebeck S, Leaman DW. Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a. Apoptosis. 2008;13:562–72.CrossRefPubMed
60.
Stawowczyk M, Van Scoy S, Kumar KP, Reich NC. The interferon stimulated gene 54 promotes apoptosis. J Biol Chem. 2011;286:7257–66.CrossRefPubMed
61.
Mullan PB, Hosey AM, Buckley NE, Quinn JE, Kennedy RD, Johnston PG, Harkin DP. The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-gamma-mediated apoptosis. Oncogene. 2005;24:5492–501.CrossRefPubMed
62.
Ferrantini M, Capone I, Belardelli F. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie. 2007;89:884–93.CrossRefPubMed
63.
Krejcova D, Prochazkova J, Kubala L, Pachernik J. Modulation of cell proliferation and differentiation of human lung carcinoma cells by the interferon-alpha. Gen Physiol Biophys. 2009;28:294–301.CrossRefPubMed
64.
Booy S, van Eijck CH, Dogan F, van Koetsveld PM, Hofland LJ. Influence of type-I Interferon receptor expression level on the response to type-I interferons in human pancreatic cancer cells. J Cell Mol Med. 2014;18:492–502.CrossRefPubMedPubMedCentral
65.
Moschos S, Kirkwood JM. Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma. Cytokine Growth Factor Rev. 2007;18:451–8.CrossRefPubMed
66.
Tate DJ, Patterson JR, Velasco-Gonzalez C, Carroll EN, Trinh J, Edwards D, Aiyar A, Finkel-Jimenez B, Zea AH. Interferon-gamma-induced nitric oxide inhibits the proliferation of murine renal cell carcinoma cells. Int J Biol Sci. 2012;8:1109–20.CrossRefPubMed
67.
Mizokami MM, Hu P, Khawli LA, Li J, Epstein AL. Chimeric TNT-3 antibody/murine interferon-gamma fusion protein for the immunotherapy of solid malignancies. Hybrid Hybridomics. 2003;22:197–207.CrossRefPubMed
68.
Akman T, Oztop I, Unek IT, Koca D, Unal OU, Salman T, Yavuzsen T, Yilmaz AU, Somali I, Demir N, Ellidokuz H. Long-term outcomes and prognostic factors of high-risk malignant melanoma patients after surgery and adjuvant high-dose interferon treatment: a single-center experience. Chemotherapy. 2015;60:228–38.CrossRef
69.
Caraglia M, Dicitore A, Marra M, Castiglioni S, Persani L, Sperlongano P, Tagliaferri P, Abbruzzese A, Vitale G. Type I interferons: ancient peptides with still under-discovered anti-cancer properties. Protein Pept Lett. 2013;20:412–23.PubMed
70.
Suarez-Kelly LP, Kemper GM, Duggan MC, Stiff A, Nole TC, Markowitz J, Luedke EA, Yildiz VO, Yu L, Jaime-Ramirez AC, et al. The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma. Oncotarget. 2016;7:81172–6.PubMed
71.
Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131–44.CrossRefPubMed
72.
Vitale G, Zappavigna S, Marra M, Dicitore A, Meschini S, Condello M, Arancia G, Castiglioni S, Maroni P, Bendinelli P, et al. The PPAR-gamma agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-beta treated pancreatic cancer cells. Biotechnol Adv. 2012;30:169–84.CrossRefPubMed
73.
Caraglia M, Marra M, Viscomi C, D’Alessandro AM, Budillon A, Meo G, Arra C, Barbieri A, Rapp UR, Baldi A, et al. The farnesyltransferase inhibitor R115777 (ZARNESTRA) enhances the pro-apoptotic activity of interferon-alpha through the inhibition of multiple survival pathways. Int J Cancer. 2007;121:2317–30.CrossRefPubMed
74.
Zhang K, Yin XF, Yang YQ, Li HL, Xu YN, Chen LY, Liu XJ, Yuan SJ, Fang XL, Xiao J, et al. A potent in vivo anti-tumor efficacy of novel recombinant type I interferon. Clin Cancer Res. 2016.
Metadata
Title
Human basonuclin 2 up-regulates a cascade set of interferon-stimulated genes with anti-cancerous properties in a lung cancer model
Authors
Egon Urgard
Anu Reigo
Eva Reinmaa
Ana Rebane
Andres Metspalu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-017-0394-x

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