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
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
September-2020 Volume 57 Issue 3

Full Size Image

Cover Legend PDF

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
September-2020 Volume 57 Issue 3

Full Size Image

Cover Legend PDF

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

  • Supplementary Files
    • Supplementary_Data.pdf
Article

GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer

  • Authors:
    • Lifang Cheng
    • Lanying Gou
    • Ting Wei
    • Jian Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
  • Pages: 858-870
    |
    Published online on: June 22, 2020
       https://doi.org/10.3892/ijo.2020.5086
  • 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

Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‑TKI), is widely applied as a first‑line treatment for non‑small cell lung cancer (NSCLC) and greatly improves the clinical outcomes of patients. However, acquired resistance to EGFR‑TKIs remains a major clinical challenge. Here, we identified guanylate‑binding protein‑1 (GBP1) as a novel protein related to erlotinib resistance, and explored the specific mechanism by which GBP1 is involved in erlotinib resistance. First, the human NSCLC cells PC9ER and HCC827ER were generated by exposing cells to increasing concentrations of erlotinib over 6 months. We screened different genes between erlotinib‑sensitive and erlotinib‑resistant cells with data from the Gene Expression Omnibus database and detected the expression of these genes in erlotinib‑resistant and erlotinib‑sensitive cells by quantitative real‑time polymerase chain reaction (qPCR). Moreover, we constructed GBP1‑knockdown and GBP1‑overexpressing cells to determine the IC50 value of erlotinib, to perform an apoptosis assay and to examine cell cycle distribution. A subcutaneous tumorigenesis test was used to analyze how GBP1 affects erlotinib resistance. Then, mass spectrometry analysis and coimmunoprecipitation were performed to verify the interaction between GBP1 and phosphoglycerate kinase 1 (PGK1). Changes in epithelial‑mesenchymal transition (EMT)‑related markers were observed following the upregulation and downregulation of PGK1 expression. Finally, a rescue experiment was used to determine whether GBP1 regulates EMT through PGK1. In the present study, GBP1 was significantly upregulated in erlotinib‑resistant cells, compared with erlotinib‑sensitive cells. In vitro and in vivo experiments showed that upregulated GBP1 expression contributed to erlotinib resistance, while decreased GBP1 expression had the opposite effect. As shown by performing survival analysis, high GBP1 expression predicted poor prognosis in patients with lung adenocarcinoma. Furthermore, the interaction between GBP1 and PGK1 was confirmed, and a rescue experiment revealed that GBP1 regulates EMT via PGK1. Finally, functional experiments showed that EMT is involved in erlotinib resistance. Our study suggests that GBP1 regulates erlotinib resistance via PGK1‑mediated EMT signaling, suggesting GBP1 as a potential therapeutic target in erlotinib‑resistant NSCLC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Jänne PA, Wang X, Socinski MA, Crawford J, Stinchcombe TE, Gu L, Capelletti M, Edelman MJ, Villalona-Calero MA, Kratzke R, et al: Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol. 30:2063–2069. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M and Riely GJ: Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 19:2240–2247. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Suda K, Rivard CJ, Mitsudomi T and Hirsch FR: Overcoming resistance to EGFR tyrosine kinase inhibitors in lung cancer, focusing on non-T790M mechanisms. Expert Rev Anticancer Ther. 17:779–786. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Westover D, Zugazagoitia J, Cho BC, Lovly CM and Paz-Ares L: Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 29(suppl_1): i10–i19. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Britzen-Laurent N, Lipnik K, Ocker M, Naschberger E, Schellerer VS, Croner RS, Vieth M, Waldner M, Steinberg P, Hohenadl C, et al: GBP-1 acts as a tumor suppressor in colorectal cancer cells. Carcinogenesis. 34:153–162. 2013. View Article : Google Scholar

7 

Yu CJ, Chang KP, Chang YJ, Hsu CW, Liang Y, Yu JS, Chi LM, Chang YS and Wu CC: Identification of guanylate-binding protein 1 as a potential oral cancer marker involved in cell invasion using omics-based analysis. J Proteome Res. 10:3778–3788. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Yamakita I, Mimae T, Tsutani Y, Miyata Y, Ito A and Okada M: Guanylate binding protein 1 (GBP-1) promotes cell motility and invasiveness of lung adenocarcinoma. Biochem Biophys Res Commun. 518:266–272. 2019. View Article : Google Scholar : PubMed/NCBI

9 

Tipton AR, Nyabuto GO, Trendel JA, Mazur TM, Wilson JP, Wadi S, Justinger JS, Moore GL, Nguyen PT and Vestal DJ: Guanylate-binding Protein-1 protects ovarian cancer cell lines but not breast cancer cell lines from killing by paclitaxel. Biochem Biophys Res Commun. 478:1617–1623. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Ji X, Zhu H, Dai X, Xi Y, Sheng Y, Gao C, Liu H, Xue Y, Liu J, Shi J, et al: Overexpression of GBP1 predicts poor prognosis and promotes tumor growth in human glioblastoma multiforme. Cancer Biomark. 25:275–290. 2019. View Article : Google Scholar

11 

Quintero M, Adamoski D, Reis LMD, Ascenção CFR, Oliveira KRS, Gonçalves KA, Dias MM, Carazzolle MF and Dias SMG: Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer. BMC Cancer. 17:7272017. View Article : Google Scholar : PubMed/NCBI

12 

Yu T, Zhao Y, Hu Z, Li J, Chu D, Zhang J, Li Z, Chen B, Zhang X, Pan H, et al: MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway. Cancer Res. 77:5782–5794. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, et al: RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun. 6:63772015. View Article : Google Scholar : PubMed/NCBI

14 

Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel Rahman M, Wang X, Levine AD, Rho JK, et al: Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 44:852–860. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Nakata A, Yoshida R, Yamaguchi R, Yamauchi M, Tamada Y, Fujita A, Shimamura T, Imoto S, Higuchi T, Nomura M, et al: Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs. Sci Rep. 5:130762015. View Article : Google Scholar

16 

Smyth GK: Limma: linear models for microarray. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Gentleman R, Carey VJ, Huber W, Irizarry RA and Dudoit S: Springer; New York, NY: pp. 397–420. 2005, View Article : Google Scholar

17 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar

18 

Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D: p21 is a universal inhibitor of cyclin kinases. Nature. 366:701–704. 1993. View Article : Google Scholar : PubMed/NCBI

19 

Massagué J: G1 cell-cycle control and cancer. Nature. 432:298–306. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Yang H, Geng YH, Wang P, Zhou YT, Yang H, Huo YF, Zhang HQ, Li Y, He HY, Tian XX, et al: Extracellular ATP promotes breast cancer invasion and epithelial-mesenchymal transition via hypoxia-inducible factor 2α signaling. Cancer Sci. 110:2456–2470. 2019.PubMed/NCBI

21 

Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 352:786–792. 2005. View Article : Google Scholar : PubMed/NCBI

22 

Oser MG, Niederst MJ, Sequist LV and Engelman JA: Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol. 16:e165–e172. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Thomas H: Colorectal cancer: CRC endothelial regulation. Nat Rev Gastro Hepat. 13:6822016. View Article : Google Scholar

24 

Wadi S, Tipton AR, Trendel JA, Khuder SA and Vestal DJ: hGBP-1 expression predicts shorter progression-free survival in ovarian cancers, while contributing to paclitaxel resistance. J Cancer Ther. 7:994–1007. 2016. View Article : Google Scholar

25 

Duan Z, Foster R, Brakora KA, Yusuf RZ and Seiden MV: GBP1 overexpression is associated with a paclitaxel resistance phenotype. Cancer Chemother Pharmacol. 57:25–33. 2006. View Article : Google Scholar

26 

Zhou JW, Tang JJ, Sun W and Wang H: PGK1 facilities cisplatin chemoresistance by triggering HSP90/ERK pathway mediated DNA repair and methylation in endometrial endometrioid adeno-carcinoma. Mol Med. 25:112019. View Article : Google Scholar

27 

Schneider CC, Archid R, Fischer N, Bühler S, Venturelli S, Berger A, Burkard M, Kirschniak A, Bachmann R, Königsrainer A, et al: Metabolic alteration–Overcoming therapy resistance in gastric cancer via PGK-1 inhibition in a combined therapy with standard chemotherapeutics. Int J Surg. 22:92–98. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Sun S, Liang X, Zhang X, Liu T, Shi Q, Song Y, Jiang Y, Wu H, Jiang Y, Lu X, et al: Phosphoglycerate kinase-1 is a predictor of poor survival and a novel prognostic biomarker of chemoresistance to paclitaxel treatment in breast cancer. Br J Cancer. 112:1332–1339. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Fu D, He C, Wei J, Zhang Z, Luo Y, Tan H and Ren C: PGK1 is a potential survival biomarker and invasion promoter by regulating the HIF-1alpha-mediated epithelial-mesenchymal transition process in breast cancer. Cell Physiol Biochem. 51:2434–2444. 2018. View Article : Google Scholar

30 

Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, et al: An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 19:279–290. 2013. View Article : Google Scholar

31 

Lou W, Chen Y, Zhu KY, Deng H, Wu T and Wang J: Polyphyllin I overcomes EMT-associated resistance to erlotinib in lung cancer cells IL-6/STAT3 pathway inhibition. Biol Pharm Bull. 40:1306–1313. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Jakobsen KR, Demuth C, Sorensen BS and Nielsen AL: The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl Lung Cancer Res. 5:172–182. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Weng CH, Chen LY, Lin YC, Shih JY, Lin YC, Tseng RY, Chiu AC, Yeh YH, Liu C, Lin YT, et al: Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene. 38:455–468. 2019. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Cheng L, Gou L, Wei T and Zhang J: GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer. Int J Oncol 57: 858-870, 2020.
APA
Cheng, L., Gou, L., Wei, T., & Zhang, J. (2020). GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer. International Journal of Oncology, 57, 858-870. https://doi.org/10.3892/ijo.2020.5086
MLA
Cheng, L., Gou, L., Wei, T., Zhang, J."GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer". International Journal of Oncology 57.3 (2020): 858-870.
Chicago
Cheng, L., Gou, L., Wei, T., Zhang, J."GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer". International Journal of Oncology 57, no. 3 (2020): 858-870. https://doi.org/10.3892/ijo.2020.5086
Copy and paste a formatted citation
x
Spandidos Publications style
Cheng L, Gou L, Wei T and Zhang J: GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer. Int J Oncol 57: 858-870, 2020.
APA
Cheng, L., Gou, L., Wei, T., & Zhang, J. (2020). GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer. International Journal of Oncology, 57, 858-870. https://doi.org/10.3892/ijo.2020.5086
MLA
Cheng, L., Gou, L., Wei, T., Zhang, J."GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer". International Journal of Oncology 57.3 (2020): 858-870.
Chicago
Cheng, L., Gou, L., Wei, T., Zhang, J."GBP1 promotes erlotinib resistance via PGK1‑activated EMT signaling in non‑small cell lung cancer". International Journal of Oncology 57, no. 3 (2020): 858-870. https://doi.org/10.3892/ijo.2020.5086
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