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
April-2019 Volume 41 Issue 4

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
April-2019 Volume 41 Issue 4

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 Open Access

Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma

  • Authors:
    • Jia Wang
    • Jie Zuo
    • Maode Wang
    • Xudong Ma
    • Ke Gao
    • Xiaobin Bai
    • Ning Wang
    • Wanfu Xie
    • Hao Liu
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2159-2167
    |
    Published online on: February 14, 2019
       https://doi.org/10.3892/or.2019.7012
  • 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

Glioblastoma (GBM) is one of the most malignant tumors in adults, associated with severe outcomes (median survival, <2 years). Multiple mechanisms are known to be involved in tumor recurrence and treatment resistance in GBM, however, the key regulator for GBM tumorigenesis and therapy resistance remains unclear. To clarify a novel potential functional mechanism of GBM recurrence, a wide range of experiments including in vitro molecular biological experiments and in vivo intracranial xenograft tumor models were performed in the present study. With bioinformatics analysis, polo‑like kinase 4 (PLK4) was initially identified as one of the most upregulated kinase encoding genes in GBM, which was functionally required for both in vitro cell proliferation and in vivo tumorigenesis in GBM. Clinically, an elevated PLK4 expression was observed in high grade glioma patients, which was associated with poor prognosis. In addition, PLK4 enhanced radioresistance in GBM, while PLK4 knockdown via lentivirus transfection significantly increased the radiosensitivity of GBM cells. Mechanically, PLK4 expression was markedly elevated by the exogenous overexpression of ATPase family AAA domain‑containing protein 2 (ATAD2) in GBM cells. Collectively, the results suggested that the ATAD2‑dependent transcriptional regulation of PLK4 promoted cell proliferation and tumorigenesis, as well as radioresistance in GBM, thus potentially inducing tumor recurrence. PLK4 could therefore serve as a potential therapeutic target for GBM treatment.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Ho VK, Reijneveld JC, Enting RH, Bienfait HP, Robe P, Baumert BG and Visser O; Dutch Society for Neuro-Oncology (LWNO), : Changing incidence and improved survival of gliomas. Eur J Cancer. 50:2309–2318. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI

3 

Signorovitch J, Li N, Ohashi E, Dastani H, Shaw J and Orsini L: Overall survival (Os), quality of life (Qol), and neurocognitive function (Nf) in recurrent glioblastoma multiforme (Gbm): A systematic literature review. Value Health. 18:A4332015. View Article : Google Scholar

4 

A PLK4 inhibitor has single-agent activity in preclinical tumor models. Cancer Discov. 4:OF112014. View Article : Google Scholar

5 

Korzeniewski N, Hohenfellner M and Duensing S: CAND1 promotes PLK4-mediated centriole overduplication and is frequently disrupted in prostate cancer. Neoplasia. 14:799–806. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Shinmura K, Kurabe N, Goto M, Yamada H, Natsume H, Konno H and Sugimura H: PLK4 overexpression and its effect on centrosome regulation and chromosome stability in human gastric cancer. Mol Biol Rep. 41:6635–6644. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Cunha-Ferreira I, Rodrigues-Martins A, Bento I, Riparbelli M, Zhang W, Laue E, Callaini G, Glover DM and Bettencourt-Dias M: The SCF/Slimb ubiquitin ligase limits centrosome amplification through degradation of SAK/PLK4. Curr Biol. 19:43–49. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Rogers GC, Rusan NM, Roberts DM, Peifer M and Rogers SL: The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication. J Cell Biol. 184:225–239. 2009. View Article : Google Scholar : PubMed/NCBI

9 

Guderian G, Westendorf J, Uldschmid A and Nigg EA: Plk4 trans-autophosphorylation regulates centriole number by controlling betaTrCP-mediated degradation. J Cell Sci. 123:2163–2169. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Holland AJ, Lan W, Niessen S, Hoover H and Cleveland DW: Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. J Cell Biol. 188:191–198. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Marina M and Saavedra HI: Nek2 and Plk4: Prognostic markers, drivers of breast tumorigenesis and drug resistance. Front Biosci. 19:352–365. 2014. View Article : Google Scholar

12 

Rosario CO, Ko MA, Haffani YZ, Gladdy RA, Paderova J, Pollett A, Squire JA, Dennis JW and Swallow CJ: Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci USA. 107:6888–6893. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Mason JM, Lin DC, Wei X, Che Y, Yao Y, Kiarash R, Cescon DW, Fletcher GC, Awrey DE, Bray MR, et al: Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 26:163–176. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Sampson PB, Liu Y, Forrest B, Cumming G, Li SW, Patel NK, Edwards L, Laufer R, Feher M, Ban F, et al: The discovery of Polo-like kinase 4 inhibitors: Identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl)-1H.indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a potent, orally active antitumor agent. J Med Chem. 58:147–169. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Yu B, Yu Z, Qi PP, Yu DQ and Liu HM: Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: Success and challenges. Eur J Med Chem. 95:35–40. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Wang J, Cheng P, Pavlyukov MS, Yu H, Zhang Z, Kim SH, Minata M, Mohyeldin A, Xie W, Chen D, et al: Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. J Clin Invest. 127:3075–3089. 2017. View Article : Google Scholar : PubMed/NCBI

17 

van Diest PJ, van Dam P, Henzen-Logmans SC, Berns E, van der Burg ME, Green J and Vergote I: A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. European organization for research and treatment of cancer-gynaecological cancer cooperative group. J Clin Pathol. 50:801–804. 1997. View Article : Google Scholar : PubMed/NCBI

18 

Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, et al: Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci USA. 110:8644–8649. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Chen C, Wang X, Xiong X, Liu Q, Huang Y, Xu Q, Hu J, Ge G and Ling K: Targeting type Igamma phosphatidylinositol phosphate kinase inhibits breast cancer metastasis. Oncogene. 34:4635–4646. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Hu J, Ahuja LG, Meharena HS, Kannan N, Kornev AP, Taylor SS and Shaw AS: Kinase regulation by hydrophobic spine assembly in cancer. Mol Cell Biol. 35:264–276. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Stransky N, Cerami E, Schalm S, Kim JL and Lengauer C: The landscape of kinase fusions in cancer. Nat Commun. 5:48462014. View Article : Google Scholar : PubMed/NCBI

22 

Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C, Nakano-Okuno M, Taylor D, Minata M, Sulman EP, et al: EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem Cell Reports. 4:226–238. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Minata M, Gu C, Joshi K, Nakano-Okuno M, Hong C, Nguyen CH, Kornblum HI, Molla A and Nakano I: Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PLoS One. 9:e925462014. View Article : Google Scholar : PubMed/NCBI

24 

Joshi K, Banasavadi-Siddegowda Y, Mo X, Kim SH, Mao P, Kig C, Nardini D, Sobol RW, Chow LM, Kornblum HI, et al: MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells. 31:1051–1063. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S and Nakano I: Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells. 31:870–881. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Habedanck R, Stierhof YD, Wilkinson CJ and Nigg EA: The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol. 7:1140–1146. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Macmillan JC, Hudson JW, Bull S, Dennis JW and Swallow CJ: Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol. 8:729–740. 2001. View Article : Google Scholar : PubMed/NCBI

28 

Dzhindzhev NS, Yu QD, Weiskopf K, Tzolovsky G, Cunha-Ferreira I, Riparbelli M, Rodrigues-Martins A, Bettencourt-Dias M, Callaini G and Glover DM: Asterless is a scaffold for the onset of centriole assembly. Nature. 467:714–718. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Li J, Tan M, Li L, Pamarthy D, Lawrence TS and Sun Y: SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia. 7:312–323. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Nakamura T, Saito H and Takekawa M: SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nat Commun. 4:17752013. View Article : Google Scholar : PubMed/NCBI

31 

Sun W, Lan X, Zhang H, Wang Z, Dong W, He L, Zhang T, Zhang P, Liu J and Qin Y: NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer. Cell Death Dis. 9:3802018. View Article : Google Scholar : PubMed/NCBI

32 

Kalashnikova EV, Revenko AS, Gemo AT, Andrews NP, Tepper CG, Zou JX, Cardiff RD, Borowsky AD and Chen HW: ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res. 70:9402–9412. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Zheng L, Li T, Zhang Y, Guo Y, Yao J, Dou L and Guo K: Oncogene ATAD2 promotes cell proliferation, invasion and migration in cervical cancer. Oncol Rep. 33:2337–2344. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Zhang M, Zhang C, Du W, Yang X and Chen Z: ATAD2 is overexpressed in gastric cancer and serves as an independent poor prognostic biomarker. Clin Transl Oncol. 18:776–781. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wang J, Zuo J, Wang M, Ma X, Gao K, Bai X, Wang N, Xie W and Liu H: Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma. Oncol Rep 41: 2159-2167, 2019.
APA
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X. ... Liu, H. (2019). Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma. Oncology Reports, 41, 2159-2167. https://doi.org/10.3892/or.2019.7012
MLA
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X., Wang, N., Xie, W., Liu, H."Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma". Oncology Reports 41.4 (2019): 2159-2167.
Chicago
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X., Wang, N., Xie, W., Liu, H."Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma". Oncology Reports 41, no. 4 (2019): 2159-2167. https://doi.org/10.3892/or.2019.7012
Copy and paste a formatted citation
x
Spandidos Publications style
Wang J, Zuo J, Wang M, Ma X, Gao K, Bai X, Wang N, Xie W and Liu H: Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma. Oncol Rep 41: 2159-2167, 2019.
APA
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X. ... Liu, H. (2019). Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma. Oncology Reports, 41, 2159-2167. https://doi.org/10.3892/or.2019.7012
MLA
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X., Wang, N., Xie, W., Liu, H."Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma". Oncology Reports 41.4 (2019): 2159-2167.
Chicago
Wang, J., Zuo, J., Wang, M., Ma, X., Gao, K., Bai, X., Wang, N., Xie, W., Liu, H."Polo‑like kinase 4 promotes tumorigenesis and induces resistance to radiotherapy in glioblastoma". Oncology Reports 41, no. 4 (2019): 2159-2167. https://doi.org/10.3892/or.2019.7012
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