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 Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
October-2019 Volume 18 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
October-2019 Volume 18 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

All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line

  • Authors:
    • Ruizhi Wang
    • Chongxiao Liu
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, 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: 3646-3654
    |
    Published online on: July 31, 2019
       https://doi.org/10.3892/ol.2019.10691
  • 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

The poor therapeutic effect of the current treatments for malignant glioma may be attributed to glioma stem cells (GSCs), which have been demonstrated to divide symmetrically. All‑trans retinoic acid (ATRA)‑induced differentiation is considered to target GSCs and has been reported to have the capability of eradicating cancer stem cells in specific malignancies. The aim of the present study was to investigate the effects of ATRA on the division mode of GSCs isolated from the U87MG glioblastoma cell line of unknown origin. The expressions of the GSC markers CD133 and nestin were detected using immunocytochemistry to identify GSCs. In addition, the differentiation potency of these GSCs was observed by detecting the expression of glial fibrillary acidic protein, β‑tubulin III and galactosylceramidase using immunofluorescent staining. The Numb protein distribution was analyzed in two daughter cells following a GSC division. The results of the present study demonstrated that Numb protein is symmetrically segregated into two daughter cells during GSC division. Furthermore, the present study demonstrated that treatment with ATRA increased the asymmetric cell division of GSCs. In conclusion, these results suggest a therapeutic effect from ATRA‑induced asymmetric division of GSCs from the U87MG cell line.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

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

2 

Johnson DR and O'Neill BP: Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 107:359–364. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Friedmann-Morvinski D, Narasimamurthy R, Xia Y, Myskiw C, Soda Y and Verma IM: Targeting NF-κB in glioblastoma: A therapeutic approach. Sci Adv. 2:e15012922016. View Article : Google Scholar : PubMed/NCBI

5 

Campos B, Wan F, Farhadi M, Ernst A, Zeppernick F, Tagscherer KE, Ahmadi R, Lohr J, Dictus C, Gdynia G, et al: Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin Cancer Res. 16:2715–2728. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Cancer Genome Atlas Research Network, . Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Sundar SJ, Hsieh JK, Manjila S, Lathia JD and Sloan A: The role of cancer stem cells in glioblastoma. Neurosurg Focus. 37:E62014. View Article : Google Scholar : PubMed/NCBI

8 

Auffinger B, Tobias AL, Han Y, Lee G, Guo D, Dey M, Lesniak MS and Ahmed AU: Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ. 21:1119–1131. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Olmez I, Shen W, McDonald H and Ozpolat B: Dedifferentiation of patient-derived glioblastoma multiforme cell lines results in a cancer stem cell-like state with mitogen-independent growth. J Cell Mol Med. 19:1262–1272. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Lathia JD, Hitomi M, Gallagher J, Gadani SP, Adkins J, Vasanji A, Liu L, Eyler CE, Heddleston JM, Wu Q, et al: Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death Dis. 2:e2002011. View Article : Google Scholar : PubMed/NCBI

11 

O'Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y, Tsatsanis A Gallinger S and Dick JE: ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell. 21:777–792. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, Bernard L, Viale G, Pelicci PG and Di Fiore PP: Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 140:62–73. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N, Hanecker P, Ayers-Ringler J, Phillips J, Siu J, et al: Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell. 20:328–340. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Zhang M, Song T, Yang L, Chen R, Wu L, Yang Z and Fang J: Nestin and CD133: Valuable stem cell-specific markers for determining clinical outcome of glioma patients. J Exp Clin Cancer Res. 27:852008. View Article : Google Scholar : PubMed/NCBI

15 

Karsy M, Albert L, Tobias ME, Murali R and Jhanwar-Uniyal M: All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 30:4915–4920. 2010.PubMed/NCBI

16 

Yu SC, Ping YF, Yi L, Zhou ZH, Chen JH, Yao XH, Gao L, Wang JM and Bian XW: Isolation and characterization of cancer stem cells from a human glioblastoma cell line U87. Cancer Lett. 265:124–134. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Sun Y, Goderie SK and Temple S: Asymmetric distribution of EGFR receptor during mitosis generates diverse CNS progenitor cells. Neuron. 45:873–886. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI

19 

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Howard CM, Valluri J, Alberico A, Julien T, Mazagri R, Marsh R, Alastair H, Cortese A, Griswold M, Wang W, et al: Analysis of Chemopredictive assay for targeting cancer stem cells in glioblastoma patients. Transl Oncol. 10:241–254. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Zheng X, Shen G, Yang X and Liu W: Most C6 cells are cancer stem cells: Evidence from clonal and population analyses. Cancer Res. 67:3691–3697. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG and Parada LF: A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 488:522–526. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Wu Y, Richard JP, Wang SD, Rath P, Laterra J and Xia S: Regulation of glioblastoma multiforme stem-like cells by inhibitor of DNA binding proteins and oligodendroglial lineage-associated transcription factors. Cancer Sci. 103:1028–1037. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Joo KM, Kim SY, Jin X, Song SY, Kong DS, Lee JI, Jeon JW, Kim MH, Kang BG, Jung Y, et al: Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest. 88:808–815. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Clement V, Dutoit V, Marino D, Dietrich PY and Radovanovic I: Limits of CD133 as a marker of glioma self-renewing cells. Int J Cancer. 125:244–248. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Wang J, Sakariassen PØ, Tsinkalovsky O, Immervoll H, Bøe SO, Svendsen A, Prestegarden L, Røsland G, Thorsen F, Stuhr L, et al: CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 122:761–768. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Barrantes-Freer A, Renovanz M, Eich M, Braukmann A, Sprang B, Spirin P, Pardo LA, Giese A and Kim EL: CD133 expression is not synonymous to immunoreactivity for AC133 and fluctuates throughout the cell cycle in glioma stem-like cells. PLoS One. 10:e01305192015. View Article : Google Scholar : PubMed/NCBI

28 

Jiang X, Xing H, Kim TM, Jung Y, Huang W, Yang HW, Song S, Park PJ, Carroll RS and Johnson MD: Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity. Stem Cells. 30:1313–1326. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Di Marcotullio L, Greco A, Mazzá D, Canettieri G, Pietrosanti L, Infante P, Coni S, Moretti M, De Smaele E, Ferretti E, et al: Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal. Oncogene. 30:65–76. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Beres BJ, George R, Lougher EJ, Barton M, Verrelli BC, McGlade CJ, Rawls JA and Wilson-Rawls J: Numb regulates Notch1, but not Notch3, during myogenesis. Mech Dev. 128:247–257. 2011. View Article : Google Scholar : PubMed/NCBI

31 

Shen Q, Zhong W, Jan YN and Temple S: Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development. 129:4843–4853. 2002.PubMed/NCBI

32 

Bajaj J, Zimdahl B and Reya T: Fearful symmetry: Subversion of asymmetric division in cancer development and progression. Cancer Res. 75:792–797. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Euskirchen P, Skaftnesmo KO, Huszthy PC, Brekkå N, Bjerkvig R, Jacobs AH and Miletic H: NUMB does not impair growth and differentiation status of experimental gliomas. Exp Cell Res. 317:2864–2873. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Beier CP and Beier D: CD133 negative cancer stem cells in glioblastoma. Front Biosci (Elite Ed). 3:701–710. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Schenk T, Stengel S and Zelent A: Unlocking the potential of retinoic acid in anticancer therapy. Br J Cancer. 111:2039–2045. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Ling GQ, Liu YJ, Ke YQ, Chen L, Jiang XD, Jiang CL and Ye W: All-trans retinoic acid impairs the vasculogenic mimicry formation ability of U87 stem-like cells through promoting differentiation. Mol Med Rep. 12:165–172. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Friedman MD, Jeevan DS, Tobias M, Murali R and Jhanwar-Uniyal M: Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid. Oncol Rep. 30:1645–1650. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Bu P, Chen KY, Lipkin SM and Shen X: Asymmetric division: A marker for cancer stem cells in early stage tumors? Oncotarget. 4:950–951. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Armstrong JL, Taylor GA, Thomas HD, Boddy AV, Redfern CP and Veal GJ: Molecular targeting of retinoic acid metabolism in neuroblastoma: The role of the CYP26 inhibitor R116010 in vitro and in vivo. Br J Cancer. 96:1675–1683. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Chakravarti N, Lotan R, Diwan AH, Warneke CL, Johnson MM and Prieto VG: Decreased expression of retinoid receptors in melanoma: Entailment in tumorigenesis and prognosis. Clin Cancer Res. 13:4817–4824. 2007. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wang R and Liu C: All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncol Lett 18: 3646-3654, 2019.
APA
Wang, R., & Liu, C. (2019). All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncology Letters, 18, 3646-3654. https://doi.org/10.3892/ol.2019.10691
MLA
Wang, R., Liu, C."All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line". Oncology Letters 18.4 (2019): 3646-3654.
Chicago
Wang, R., Liu, C."All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line". Oncology Letters 18, no. 4 (2019): 3646-3654. https://doi.org/10.3892/ol.2019.10691
Copy and paste a formatted citation
x
Spandidos Publications style
Wang R and Liu C: All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncol Lett 18: 3646-3654, 2019.
APA
Wang, R., & Liu, C. (2019). All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncology Letters, 18, 3646-3654. https://doi.org/10.3892/ol.2019.10691
MLA
Wang, R., Liu, C."All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line". Oncology Letters 18.4 (2019): 3646-3654.
Chicago
Wang, R., Liu, C."All‑trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line". Oncology Letters 18, no. 4 (2019): 3646-3654. https://doi.org/10.3892/ol.2019.10691
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