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 Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
October-2015 Volume 36 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-2015 Volume 36 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

Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells

  • Authors:
    • Rong-Jing Zhou
    • Xiong-Ying Xu
    • Bu-Xing Liu
    • Wen-Zhen Dai
    • Mei-Qin Cai
    • Chun-Feng Bai
    • Xian-Fei Zhang
    • Li-Min Wang
    • Li Lin
    • Shu-Zhen Jia
    • Wen-Hua Wang
  • View Affiliations / Copyright

    Affiliations: Luqiao Hospital of Taizhou Enze Medical Center (Group), Taizhou, Zhejiang 318050, P.R. China
  • Pages: 1159-1164
    |
    Published online on: August 13, 2015
       https://doi.org/10.3892/ijmm.2015.2312
  • 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 constitutive activation of signal transducer and activator of transcription 3 (STAT3) contributes to resistance to temozolomide (TMZ) in glioblastoma multiforme (GBM). The aim of this study was to explore the biological role of microRNA-31 (miR-31) in GBM, particularly its role in the regulation of TMZ chemosensitivity. For this purpose, the human GBM cell lines, U251 and U87, were transfected with a miR-31 precursor (pre-miR-31), and cell proliferation, apoptosis and STAT3 phosphorylation were then assessed. To evaluate the effects of miR-31 on TMZ cytotoxicity, the cells were transfected with pre-miR-31 and exposed to 100 µM TMZ for 72 h prior to cell proliferation and apoptosis analysis. A constitutively active STAT3 mutant was co-transfected with pre-miR-31 into the cells to confirm the mediating role of STAT3 signaling. The enforced expression of miR-31 significantly reduced cell proliferation and induced mitochondrial apoptosis, as manifested by the loss of mitochondrial membrane potential and the increase in caspase-9 and caspase-3 activity. The phosphorylation level of STAT3 was significantly decreased by the overexpression of miR-31. The co-delivery of the constitutively active STAT3 mutant blocked the tumor suppressive effects of miR-31. In addition, miR-31 overexpression significantly enhanced the cytotoxic effects of TMZ on the GBM cells, as evidenced by the accelerated suppression of cell proliferation and the induction of apoptosis. The chemosensitizing effects of miR-31 were significantly impaired by the expression of the constitutively active STAT3 mutant. Taken together, our results indicate that miR-31 triggers mitochondrial apoptosis and potentiates TMZ cytotoxicity in GBM cells largely through the suppression of STAT3 activation. Thus, the restoration of miR-31 expression may be of therapeutic beenefit in the treatment of GBM.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Wilson TA, Karajannis MA and Harter DH: Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int. 5:642014. View Article : Google Scholar : PubMed/NCBI

2 

Alifieris C and Trafalis DT: Glioblastoma multiforme: Pathogenesis and treatment. Pharmacol Ther. 152:63–82. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Hart MG, Garside R, Rogers G, Stein K and Grant R: Temozolomide for high grade glioma. Cochrane Database Syst Rev. 4:CD0074152013.PubMed/NCBI

4 

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Hau P, Koch D, Hundsberger T, Marg E, Bauer B, Rudolph R, Rauch M, Brenner A, Rieckmann P, Schuth J, et al: Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology. 68:688–690. 2007. View Article : Google Scholar : PubMed/NCBI

6 

do Carmo A, Balça-Silva J, Matias D and Lopes MC: PKC signaling in glioblastoma. Cancer Biol Ther. 14:287–294. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Fan QW and Weiss WA: Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol. 347:279–296. 2010.PubMed/NCBI

9 

Luwor RB, Stylli SS and Kaye AH: The role of Stat3 in glioblastoma multiforme. J Clin Neurosci. 20:907–911. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Kohsaka S, Wang L, Yachi K, Mahabir R, Narita T, Itoh T, Tanino M, Kimura T, Nishihara H and Tanaka S: STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. Mol Cancer Ther. 11:1289–1299. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Fabbri M: MicroRNAs and cancer: towards a personalized medicine. Curr Mol Med. 13:751–756. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Williams AE: Functional aspects of animal microRNAs. Cell Mol Life Sci. 65:545–562. 2008. View Article : Google Scholar

13 

Wang S, Li Q, Wang K, Dai Y, Yang J, Xue S, Han F, Zhang Q, Liu J and Wu W: Decreased expression of microRNA-31 associates with aggressive tumor progression and poor prognosis in patients with bladder cancer. Clin Transl Oncol. 15:849–854. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Asangani IA, Harms PW, Dodson L, Pandhi M, Kunju LP, Maher CA, Fullen DR, Johnson TM, Giordano TJ, Palanisamy N and Chinnaiyan AM: Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget. 3:1011–1025. 2012.PubMed/NCBI

15 

Nosho K, Igarashi H, Nojima M, Ito M, Maruyama R, Yoshii S, Naito T, Sukawa Y, Mikami M, Sumioka W, et al: Association of microRNA-31 with BRAF mutation, colorectal cancer survival and serrated pathway. Carcinogenesis. 35:776–783. 2014. View Article : Google Scholar

16 

Wang S, Jiao B, Geng S, Song J, Liang Z and Lu S: Concomitant microRNA-31 downregulation and radixin upregulation predicts advanced tumor progression and unfavorable prognosis in patients with gliomas. J Neurol Sci. 338:71–76. 2014. View Article : Google Scholar : PubMed/NCBI

17 

Li T, Luo W, Liu K, Lv X and Xi T: miR-31 promotes proliferation of colon cancer cells by targeting E2F2. Biotechnol Lett. 37:523–532. 2015. View Article : Google Scholar

18 

Huang S, Wu B, Li D, Zhou W, Deng G, Zhang K and Li Y: Knockdown of astrocyte elevated gene-1 inhibits tumor growth and modifies microRNAs expression profiles in human colorectal cancer cells. Biochem Biophys Res Commun. 444:338–345. 2014. View Article : Google Scholar : PubMed/NCBI

19 

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

20 

Pilati C, Amessou M, Bihl MP, Balabaud C, Nhieu JT, Paradis V, Nault JC, Izard T, Bioulac-Sage P, Couchy G, et al: Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med. 208:1359–1366. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Filippi-Chiela EC, Thomé MP, Bueno e Silva MM, Pelegrini AL, Ledur PF, Garicochea B, Zamin LL and Lenz G: Resveratrol abrogates the temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells. BMC Cancer. 13:1472013. View Article : Google Scholar : PubMed/NCBI

22 

Chen L, Wang X, Wang H, Li Y, Yan W, Han L, Zhang K, Zhang J, Wang Y, Feng Y, et al: miR-137 is frequently downregulated in glioblastoma and is a negative regulator of Cox-2. Eur J Cancer. 48:3104–3111. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Yue X, Wang P, Xu J, Zhu Y, Sun G, Pang Q and Tao R: MicroRNA-205 functions as a tumor suppressor in human glioblastoma cells by targeting VEGF-A. Oncol Rep. 27:1200–1206. 2012.

24 

Zhang QQ, Xu H, Huang MB, Ma LM, Huang QJ, Yao Q, Zhou H and Qu LH: MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. Neuro Oncol. 14:278–287. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Körner C, Keklikoglou I, Bender C, Wörner A, Münstermann E and Wiemann S: MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon). J Biol Chem. 288:8750–8761. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Mitamura T, Watari H, Wang L, Kanno H, Kitagawa M, Hassan MK, Kimura T, Tanino M, Nishihara H, Tanaka S and Sakuragi N: microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway. Mol Cancer. 13:972014. View Article : Google Scholar : PubMed/NCBI

27 

Dong Z, Zhong Z, Yang L, Wang S and Gong Z: MicroRNA-31 inhibits cisplatin-induced apoptosis in non-small cell lung cancer cells by regulating the drug transporter ABCB9. Cancer Lett. 343:249–257. 2014. View Article : Google Scholar

28 

McFarland BC, Hong SW, Rajbhandari R, Twitty GB Jr, Gray GK, Yu H, Benveniste EN and Nozell SE: NF-κB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma. PLoS One. 8:e787282013. View Article : Google Scholar

29 

Swiatek-Machado K, Mieczkowski J, Ellert-Miklaszewska A, Swierk P, Fokt I, Szymanski S, Skora S, Szeja W, Grynkiewicz G, Lesyng B, et al: Novel small molecular inhibitors disrupt the JAK/STAT3 and FAK signaling pathways and exhibit a potent antitumor activity in glioma cells. Cancer Biol Ther. 13:657–670. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Wang J, Wang Q, Cui Y, Liu ZY, Zhao W, Wang CL, Dong Y, Hou L, Hu G, Luo C, et al: Knockdown of cyclin D1 inhibits proliferation, induces apoptosis, and attenuates the invasive capacity of human glioblastoma cells. J Neurooncol. 106:473–484. 2012. View Article : Google Scholar

31 

Premkumar DR, Jane EP, Foster KA and Pollack IF: Survivin inhibitor YM-155 sensitizes tumor necrosis factor- related apoptosis-inducing ligand-resistant glioma cells to apoptosis through Mcl-1 downregulation and by engaging the mitochondrial death pathway. J Pharmacol Exp Ther. 346:201–210. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Lo HW, Cao X, Zhu H and Ali-Osman F: Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res. 14:6042–6054. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Mitamura T, Watari H, Wang L, Kanno H, Hassan MK, Miyazaki M, Katoh Y, Kimura T, Tanino M, Nishihara H, et al: Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. Oncogenesis. 2:e402013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zhou R, Xu X, Liu B, Dai W, Cai M, Bai C, Zhang X, Wang L, Lin L, Jia S, Jia S, et al: Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells. Int J Mol Med 36: 1159-1164, 2015.
APA
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C. ... Wang, W. (2015). Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells. International Journal of Molecular Medicine, 36, 1159-1164. https://doi.org/10.3892/ijmm.2015.2312
MLA
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C., Zhang, X., Wang, L., Lin, L., Jia, S., Wang, W."Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells". International Journal of Molecular Medicine 36.4 (2015): 1159-1164.
Chicago
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C., Zhang, X., Wang, L., Lin, L., Jia, S., Wang, W."Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells". International Journal of Molecular Medicine 36, no. 4 (2015): 1159-1164. https://doi.org/10.3892/ijmm.2015.2312
Copy and paste a formatted citation
x
Spandidos Publications style
Zhou R, Xu X, Liu B, Dai W, Cai M, Bai C, Zhang X, Wang L, Lin L, Jia S, Jia S, et al: Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells. Int J Mol Med 36: 1159-1164, 2015.
APA
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C. ... Wang, W. (2015). Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells. International Journal of Molecular Medicine, 36, 1159-1164. https://doi.org/10.3892/ijmm.2015.2312
MLA
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C., Zhang, X., Wang, L., Lin, L., Jia, S., Wang, W."Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells". International Journal of Molecular Medicine 36.4 (2015): 1159-1164.
Chicago
Zhou, R., Xu, X., Liu, B., Dai, W., Cai, M., Bai, C., Zhang, X., Wang, L., Lin, L., Jia, S., Wang, W."Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells". International Journal of Molecular Medicine 36, no. 4 (2015): 1159-1164. https://doi.org/10.3892/ijmm.2015.2312
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