Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
February-2016 Volume 35 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
February-2016 Volume 35 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines

  • Authors:
    • Zhaohui Li
    • Qingwei Li
    • Liang Han
    • Nan Tian
    • Qianlei Liang
    • Yanzhe Li
    • Xingli Zhao
    • Chao Du
    • Yu Tian
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130031, P.R. China, Department of Neurosurgery, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150036, P.R. China, Department of Cell Biology, College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
  • Pages: 1013-1019
    |
    Published online on: November 30, 2015
       https://doi.org/10.3892/or.2015.4465
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Alternative splicing is a near-ubiquitous phenomenon with important roles in human diseases, including cancers. Splice-switching oligonucleotides (SSOs) have emerged as a class of antisense therapeutics that modulate alternative splicing by hybridizing to the pre-mRNA splice site. The Bcl-x gene is alternatively spliced to express anti‑apoptotic Bcl-xL and pro-apoptotic Bcl-xS. Bcl-xL expression is upregulated in many cancers and is considered a general mechanism by which cancer cells evade apoptosis. By redirecting Bcl-x pre-mRNA splicing from Bcl-xL to Bcl-xS, SSO exerted pro-apoptotic and chemosensitizing effects in various cancer cell lines. In this study, we investigated the effects of SSO targeting Bcl-x pre-mRNA in human glioma cell lines. First, we performed reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine the mRNA and protein expression levels of Bcl-xL in glioma cell lines (U87 and U251) and a normal human astrocyte cell line (HA1800). Then, the Bcl-x SSO was designed to bind to the downstream 5' alternative splice site of exon 2 in Bcl-x pre-mRNA and was modified using 2'-O-methoxyethyl-phosphorothioate. An oligonucleotide targeting aberrantly spliced human β-globin intron was used as a negative control. The SSOs were delivered with a cationic lipid into glioma and astrocyte cell lines. The antitumor effects of the SSOs were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and flow cytometry, and the switch in production from Bcl-xL to Bcl-xS was analyzed by RT-PCR and western blotting. Bcl-xL mRNA and protein were highly expressed in both glioma cell lines. The Bcl-x SSO modified Bcl-x pre-mRNA splicing and had pro-apoptotic effects on the glioma cell lines. By contrast, the lipid alone and the control SSO did not affect Bcl-xL expression or induce apoptosis. Our study demonstrated the antitumor activity of an SSO that targets Bcl-x pre-mRNA splicing in glioma cell lines. Bcl-x SSO may be a potential strategy for treating gliomas.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Nilsen TW and Graveley BR: Expansion of the eukaryotic proteome by alternative splicing. Nature. 463:457–463. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Gamazon ER and Stranger BE: Genomics of alternative splicing: Evolution, development and pathophysiology. Hum Genet. 133:679–687. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, et al: The landscape of somatic copy-number alteration across human cancers. Nature. 463:899–905. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Kalsotra A and Cooper TA: Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet. 12:715–729. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Barta A and Schümperli D: Editorial on alternative splicing and disease. RNA Biol. 7:388–389. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Oltean S and Bates DO: Hallmarks of alternative splicing in cancer. Oncogene. 33:5311–5318. 2014. View Article : Google Scholar

7 

Pal S, Gupta R and Davuluri RV: Alternative transcription and alternative splicing in cancer. Pharmacol Ther. 136:283–294. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Mercatante DR, Bortner CD, Cidlowski JA and Kole R: Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. Analysis of apoptosis and cell death. J Biol Chem. 276:16411–16417. 2001. View Article : Google Scholar : PubMed/NCBI

10 

Palve V, Mallick S, Ghaisas G, Kannan S and Teni T: Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers. PLoS One. 9:e1119272014. View Article : Google Scholar : PubMed/NCBI

11 

Vegran F, Boidot R, Oudin C, Riedinger JM and Lizard-Nacol S: Distinct expression of Survivin splice variants in breast carcinomas. Int J Oncol. 27:1151–1157. 2005.PubMed/NCBI

12 

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, et al Australian Cancer Study; Australian Ovarian Cancer Study; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab); Gene Environment interaction and Breast Cancer (GENICA); Swedish Breast Cancer Study (SWE-BRCA); Hereditary Breast and Ovarian Cancer Research group Netherlands (HEBON); Epidemiological study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE); Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO): Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 45:371–384. e1–e2. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, Zhu S, Gu Y, Villa GR, Akhavan D, et al: EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab. 17:1000–1008. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Singh A, Karnoub AE, Palmby TR, Lengyel E, Sondek J and Der CJ: Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene. 23:9369–9380. 2004. View Article : Google Scholar : PubMed/NCBI

15 

Mayer S, Hirschfeld M, Jaeger M, Pies S, Iborra S, Erbes T and Stickeler E: RON alternative splicing regulation in primary ovarian cancer. Oncol Rep. 34:423–430. 2015.PubMed/NCBI

16 

Matsuyama M, Chijiwa T, Inoue Y, Abe Y, Nishi M, Miyazaki N, Furukawa D, Mukai M, Suemizu H, Sekido Y, et al: Alternative splicing variant of vascular endothelial growth factor-A is a critical prognostic factor in non-small cell lung cancer. Oncol Rep. 22:1407–1413. 2009.PubMed/NCBI

17 

David CJ, Chen M, Assanah M, Canoll P and Manley JL: HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 463:364–368. 2010. View Article : Google Scholar :

18 

Kim YJ and Kim HS: Alternative splicing and its impact as a cancer diagnostic marker. Genomics Inform. 10:74–80. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, Mrugala MM, Jensen R, Baehring JM, Sloan A, et al: A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: The ACT III study. Neuro Oncol. 17:854–861. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Chen J and Weiss WA: Alternative splicing in cancer: Implications for biology and therapy. Oncogene. 34:1–14. 2015. View Article : Google Scholar

21 

Bonomi S, Gallo S, Catillo M, Pignataro D, Biamonti G and Ghigna C: Oncogenic alternative splicing switches: Role in cancer progression and prospects for therapy. Int J Cell Biol. 2013:9620382013. View Article : Google Scholar : PubMed/NCBI

22 

Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, et al: Local restoration of dystrophin expression with the morpholino oligomer AVi-4658 in Duchenne muscular dystrophy: A single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 8:918–928. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Moore MJ, Wang Q, Kennedy CJ and Silver PA: An alternative splicing network links cell-cycle control to apoptosis. Cell. 142:625–636. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Miura K, Fujibuchi W and Unno M: Splice variants in apoptotic pathway. Exp Oncol. 34:212–217. 2012.PubMed/NCBI

25 

Mercatante DR, Mohler JL and Kole R: Cellular response to an antisense-mediated shift of Bcl-x pre-mRNA splicing and anti-neoplastic agents. J Biol Chem. 277:49374–49382. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Bauman JA, Li SD, Yang A, Huang L and Kole R: Anti-tumor activity of splice-switching oligonucleotides. Nucleic Acids Res. 38:8348–8356. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Bauman J, Jearawiriyapaisarn N and Kole R: Therapeutic potential of splice-switching oligonucleotides. Oligonucleotides. 19:1–13. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Weiler M, Bähr O, Hohlweg U, Naumann U, Rieger J, Huang H, Tabatabai G, Krell HW, Ohgaki H, Weller M, et al: BCL-xL: Time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells. Cell Death Differ. 13:1156–1169. 2006. View Article : Google Scholar

29 

Alexandru-Abrams D, Jadus MR, Hsu FP, Stathopoulos A and Bota DA: Therapeutic targeting of malignant glioma. Anticancer Agents Med Chem. 14:1075–1084. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Li Z, Tian Y, Tian N, Zhao X, Du C, Han L and Zhang H: Aberrant alternative splicing pattern of ADAR2 downregulates adenosine-to-inosine editing in glioma. Oncol Rep. 33:2845–2852. 2015.PubMed/NCBI

31 

Fontana L, Rovina D, Novielli C, Maffioli E, Tedeschi G, Magnani I and Larizza L: Suggestive evidence on the involvement of polypyrimidine-tract binding protein in regulating alternative splicing of MAP/microtubule affinity-regulating kinase 4 in glioma. Cancer Lett. 359:87–96. 2015. View Article : Google Scholar : PubMed/NCBI

32 

Disterer P, Kryczka A, Liu Y, Badi YE, Wong JJ, Owen JS and Khoo B: Development of therapeutic splice-switching oligo-nucleotides. Hum Gene Ther. 25:587–598. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Sazani P, Astriab-Fischer A and Kole R: Effects of base modifications on antisense properties of 2′-O-methoxyethyl and PNA oligonucleotides. Antisense Nucleic Acid Drug Dev. 13:119–128. 2003. View Article : Google Scholar

34 

Adkin C, Fletcher S and Wilton SD: Optimizing splice-switching oligomer sequences using 2′-O-methyl phosphorothioate chemistry. Methods Mol Biol. 867:169–188. 2012. View Article : Google Scholar

35 

Wan J, Bauman JA, Graziewicz MA, Sazani P and Kole R: Oligonucleotide therapeutics in cancer. Cancer Treat Res. 158:213–233. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Shchelkunova A, Ermolinsky B, Boyle M, Mendez I, Lehker M, Martirosyan KS and Kazansky AV: Tuning of alternative splicing - switch from proto-oncogene to tumor suppressor. Int J Biol Sci. 9:45–54. 2013. View Article : Google Scholar :

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Li Z, Li Q, Han L, Tian N, Liang Q, Li Y, Zhao X, Du C and Tian Y: Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines. Oncol Rep 35: 1013-1019, 2016.
APA
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y. ... Tian, Y. (2016). Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines. Oncology Reports, 35, 1013-1019. https://doi.org/10.3892/or.2015.4465
MLA
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y., Zhao, X., Du, C., Tian, Y."Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines". Oncology Reports 35.2 (2016): 1013-1019.
Chicago
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y., Zhao, X., Du, C., Tian, Y."Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines". Oncology Reports 35, no. 2 (2016): 1013-1019. https://doi.org/10.3892/or.2015.4465
Copy and paste a formatted citation
x
Spandidos Publications style
Li Z, Li Q, Han L, Tian N, Liang Q, Li Y, Zhao X, Du C and Tian Y: Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines. Oncol Rep 35: 1013-1019, 2016.
APA
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y. ... Tian, Y. (2016). Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines. Oncology Reports, 35, 1013-1019. https://doi.org/10.3892/or.2015.4465
MLA
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y., Zhao, X., Du, C., Tian, Y."Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines". Oncology Reports 35.2 (2016): 1013-1019.
Chicago
Li, Z., Li, Q., Han, L., Tian, N., Liang, Q., Li, Y., Zhao, X., Du, C., Tian, Y."Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines". Oncology Reports 35, no. 2 (2016): 1013-1019. https://doi.org/10.3892/or.2015.4465
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team