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
August 2012 Volume 28 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

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

International Journal of Oncology

International Journal of Oncology

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

Molecular Medicine Reports

Molecular Medicine Reports

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

Oncology Reports

Oncology Reports

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

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

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

Oncology Letters

Oncology Letters

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

Biomedical Reports

Biomedical Reports

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

Molecular and Clinical Oncology

Molecular and Clinical Oncology

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

World Academy of Sciences Journal

World Academy of Sciences Journal

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

International Journal of Functional Nutrition

International Journal of Functional Nutrition

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

International Journal of Epigenetics

International Journal of Epigenetics

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

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
August 2012 Volume 28 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

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

Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion

  • Authors:
    • Lingyun Zhu
    • Xiudong Wang
    • Jie Wu
    • Dekui Mao
    • Zhishan Xu
    • Ziyang He
    • Aiping Yu
  • View Affiliations / Copyright

    Affiliations: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China
  • Pages: 553-560
    |
    Published online on: June 1, 2012
       https://doi.org/10.3892/or.2012.1851
  • 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

Protease-activated receptor 1 (PAR1) and integrins play an important role in thrombin-mediated tumor cell invasion. However, the role of PAR1 and integrin ανβ5 and the relationship between the two receptors in thrombin-induced lung cancer invasion remains unknown. Moreover, the mechanisms through which immobilized thrombin facilitates tumor invasion are poorly understood. In this study, both native and immobilized thrombin promoted lung cancer cell adhesion, migration and extracellular signal-regulated kinase phosphorylation. Integrin ανβ5 is involved in both native and immobilized thrombin-mediated tumor cell invasion; PAR1 had no effect on immobilized thrombin-mediated cell invasion. PAR1 and integrin ανβ5 colocalized on the surface of native thrombin-treated cells. This study suggests that targeting of integrin ανβ5 or the PAR1-integrin ανβ5 complex may present an important therapeutic opportunity to prevent lung cancer invasion.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Rickels FR, Levine M and Edwards RL: Hemostatic alterations in cancer patients. Cancer Metastasis Rev. 11:237–248. 1992. View Article : Google Scholar

2 

Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM and Melton LJ III: Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 160:809–815. 2000. View Article : Google Scholar : PubMed/NCBI

3 

Kasthuri R, Taubman M and Mackman N: Role of tissue factor in cancer. J Clin Oncol. 27:4834–4838. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Amirkhosravi A, Meyer T, Amaya M, Davila M, Mousa SA, Robson T and Francis JL: The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin Thromb Hemost. 33:643–652. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Liu Y, Jiang P, Capkova K, Xue D, Ye L, Sinha SC, Mackman N, Janda KD and Liu C: Tissue factor-activated coagulation cascade in the tumor microenvironment is critical for tumor progression and an effective target for therapy. Cancer Res. 71:6492–6502. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Hron G, Kollars M, Binder BR, Eichinger S and Kyrle PA: Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA. 296:397–402. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Zigler M, Kamiya T, Brantley EC, Villares GJ and Bar-Eli M: PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis. Cancer Res. 71:6561–6566. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM and Stump DC: Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ. Am J Clin Pathol. 93:516–521. 1990.PubMed/NCBI

9 

Zacharski LR, Memoli VA, Morain WD, Schlaeppi JM and Rousseau SM: Cellular localization of enzymatically active thrombin in intact human tissues by hirudin binding. Thromb Haemost. 73:793–797. 1995.PubMed/NCBI

10 

Ornstein DL and Zacharski LR: Treatment of cancer with anticoagulants: rationale in the treatment of melanoma. Int J Hematol. 73:157–161. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginzburg Y, Reich R, Vlodavsky I and Bar-Shavit R: Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med. 4:909–914. 1998. View Article : Google Scholar : PubMed/NCBI

12 

Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U and Bar-Shavit R: Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Int J Cancer. 113:372–378. 2005. View Article : Google Scholar

13 

Henrikson KP, Salazar SL, Fenton JW II and Pentecost BT: Role of thrombin receptor in breast cancer invasiveness. Br J Cancer. 79:401–406. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Radjabi AR, Sawada K, Jagadeeswaran S, Eichbichler A, Kenny HA, Montag A, Bruno K and Lengyel E: Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 and beta1-integrin on the cell surface. J Biol Chem. 283:2822–2834. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Yang RS, Chiang HS, Tang CH, Yeh CS and Huang TF: Rhodostomin inhibits thrombin-enhanced adhesion of ROS 17/2.8 cells through the blockade of alphavbeta3 integrin. Toxicon. 46:387–393. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Even-Ram SC, Maoz M, Pokroy E, Reich R, Katz BZ, Gutweini P, Altevogti P and Bar-Shavit R: Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the alpha v beta 5 integrin. J Biol Chem. 276:10952–10962. 2001. View Article : Google Scholar : PubMed/NCBI

17 

Chiang HS, Yang RS and Huang TF: Thrombin enhances the adhesion and migration of human colon adenocarcinoma cells via increased beta 3-integrin expression on the tumor cell surface and their inhibition by the snake venom peptide, rhodostomin. Br J Cancer. 73:902–908. 1996. View Article : Google Scholar

18 

Chiang HS, Yang RS and Huang TF: The Arg-Gly-Asp-containing peptide, rhodostomin, inhibits in vitro cell adhesion to extracellular matrices and platelet aggregation caused by Saos-2 human osteosarcoma cells. Br J Cancer. 71:265–270. 1995. View Article : Google Scholar

19 

Bode W, Turk D and Karshikov A: The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci. 1:426–471. 1992. View Article : Google Scholar

20 

Bar-Shavit R, Sabbah V, Lampugnani MG, Marchisio PC, Fenton JW II, Vlodavsky I and Dejana E: An Arg-Gly-Asp sequence within thrombin promotes endothelial cell adhesion. J Cell Biol. 112:335–344. 1991. View Article : Google Scholar : PubMed/NCBI

21 

Bar-Shavit R, Eskohjido Y, Fenton JW II, Esko JD and Vlodavsky I: Thrombin adhesive properties: induction by plasmin and heparan sulfate. J Cell Biol. 123:1279–1287. 1993. View Article : Google Scholar : PubMed/NCBI

22 

Tsopanoglou NE, Andriopoulou P and Maragoudakis ME: On the mechanism of thrombin-induced angiogenesis: involvement of alphavbeta3-integrin. Am J Physiol Cell Physiol. 283:C1501–C1510. 2002. View Article : Google Scholar : PubMed/NCBI

23 

Tsopanoglou NE, Papaconstantinou ME, Flordellis CS and Maragoudakis ME: On the mode of action of thrombin-induced angiogenesis: thrombin peptide, TP508, mediates effects in endothelial cells via alphavbeta3 integrin. Thromb Haemost. 92:846–857. 2004.PubMed/NCBI

24 

Sajid M, Zhao R, Pathak A, Smyth SS and Stouffer GA: Alphavbeta3-integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells. Am J Physiol Cell Physiol. 285:C1330–C1338. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Papaconstantinou ME, Carrell CJ, Pineda AO, Bobofchak KM, Mathews FS, Flordellis CS, Maragoudakis ME, Tsopanoglou NE and Di Cera E: Thrombin functions through its RGD sequence in a non-canonical conformation. J Biol Chem. 280:29393–29396. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Bar-Shavit R, Eldor A and Vlodavsky I: Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest. 84:1096–1104. 1989. View Article : Google Scholar : PubMed/NCBI

27 

Hernández-Rodríguez NA, Correa E, Sotelo R, Gómez-Ruiz C, Contreras-Paredes A and Green L: Thrombin is present in the lungs of patients with primary extremity osteosarcoma and pulmonary metastases. Int J Biol Markers. 17:189–195. 2002.PubMed/NCBI

28 

Fenton JW II: Regulation of thrombin generation and functions. Semin Thromb Hemost. 14:234–240. 1988. View Article : Google Scholar : PubMed/NCBI

29 

Weitz JI, Hudoba M, Massel D, Maraganore J and Hirsh J: Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 86:385–391. 1990. View Article : Google Scholar : PubMed/NCBI

30 

Begonja AJ, Geiger J, Rukoyatkina N, Rauchfuss S, Gambaryan S and Walter U: Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxaneA2 and inhibited by cGMP/cGMP-dependent protein kinase. Blood. 109:616–618. 2007. View Article : Google Scholar : PubMed/NCBI

31 

Malaver E, Romaniuk MA, D’atri LP, Pozner RG, Negrotto S, Benzadón R and Schattner M: NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost. 7:1333–1343. 2009. View Article : Google Scholar : PubMed/NCBI

32 

Shankar H, Garcia A, Prabhakar J, Kim S and Kunapull SP: P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost. 4:638–647. 2006. View Article : Google Scholar

33 

Liu J, Schuff-Werner P and Steiner M: Thrombin/thrombin receptor (PAR-1)-mediated induction of IL-8 and VEGF expression in prostate cancer cells. Biochem Biophys Res Commun. 343:183–189. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Chang LH, Chen CH, Huang DY, Pai HC, Pan SL and Teng CM: Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells. J Cell Physiol. 226:1060–1068. 2011.PubMed/NCBI

35 

Sil H, Sen T and Chatterjee A: Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9. Oncol Res. 19:335–348. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Hu CT, Wu JR, Cheng CC, Wang S, Wang HT, Lee MC, Wang LJ, Pan SM, Chang TY and Wu WS: Reactive oxygen species-mediated PKC and integrin signaling promotes tumor progression of human hepatoma HepG2. Clin Exp Metastasis. 28:851–863. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Sood AK, Fletcher MS, Coffin JE, Yang M, Seftor EA, Gruman LM, Gershenson DM and Hendrix MJC: Functional role of matrix metalloproteinases in tumor cell plasticity. Am J Obstet Gynecol. 190:899–909. 2004. View Article : Google Scholar : PubMed/NCBI

38 

Sharma N, Seftor RE, Seftor EA, Gruman LM, Heidger PM Jr, Cohen MB, Lubaroff DM and Hendrix MJ: Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry. Prostate. 50:189–201. 2002. View Article : Google Scholar

39 

Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L and Kuliopulos A: Blocking the protease-activated receptor 1–4 heterodimer in platelet-mediated thrombosis. Circulation. 113:1244–1254. 2006.

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zhu L, Wang X, Wu J, Mao D, Xu Z, He Z and Yu A: Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion. Oncol Rep 28: 553-560, 2012.
APA
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., & Yu, A. (2012). Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion. Oncology Reports, 28, 553-560. https://doi.org/10.3892/or.2012.1851
MLA
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., Yu, A."Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion". Oncology Reports 28.2 (2012): 553-560.
Chicago
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., Yu, A."Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion". Oncology Reports 28, no. 2 (2012): 553-560. https://doi.org/10.3892/or.2012.1851
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu L, Wang X, Wu J, Mao D, Xu Z, He Z and Yu A: Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion. Oncol Rep 28: 553-560, 2012.
APA
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., & Yu, A. (2012). Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion. Oncology Reports, 28, 553-560. https://doi.org/10.3892/or.2012.1851
MLA
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., Yu, A."Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion". Oncology Reports 28.2 (2012): 553-560.
Chicago
Zhu, L., Wang, X., Wu, J., Mao, D., Xu, Z., He, Z., Yu, A."Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion". Oncology Reports 28, no. 2 (2012): 553-560. https://doi.org/10.3892/or.2012.1851
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