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
May 2013 Volume 29 Issue 5

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
May 2013 Volume 29 Issue 5

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

Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells

  • Authors:
    • Wei Chen
    • Huali Zhang
    • Jiandong Wang
    • Gang Cao
    • Zhen Dong
    • Han Su
    • Xiaojun Zhou
    • Senlin Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Stomatology, Nanjing Jinling Hospital, Nanjing University, School of Medicine, Nanjing, Jiangsu, P.R. China, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China, Department of Pathology, Nanjing Jinling Hospital, Nanjing University, School of Medicine, Nanjing, Jiangsu, P.R. China
  • Pages: 1797-1804
    |
    Published online on: February 28, 2013
       https://doi.org/10.3892/or.2013.2317
  • 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

Salivary adenoid cystic carcinoma (SACC) is a common type of salivary gland cancer. The poor long-term prognosis for patients with SACC is mainly due to local recurrence, perineural invasion (PNI) and distant metastasis. Notch signaling plays a critical role in determining cell fate such as proliferation, differentiation and apoptosis. Accumulating evidence indicates that aberrant Notch-4 expression has a tumor-promoting function in SACC. In the present study, we used lentiviral-mediated RNA interference (RNAi) targeted against Notch-4 to determine the effects of decreased levels of this protein in the human highly metastatic adenoid cystic carcinoma cell line ACC-M. Furthermore, the proliferative capability as well as the PNI potential of the treated cells were observed in vitro. Our studies demonstrated that RNAi directed against Notch-4 markedly decreased Notch-4 gene expression, resulting in the inhibition of cell proliferation, and G0/G1 to S phase arrest in ACC-M cells. Knockdown of Notch-4 also resulted in a decrease in the in vitro PNI activity in ACC-M cells. To conclude, RNAi targeting against Notch-4 induces the suppression of cell growth and inhibition of PNI in vitro in ACC-M cells. Notch-4 may play an important role in regulating proliferation and PNI activity of SACC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Renehan A, Gleave EN, Hancock BD, Smith P and McGurk M: Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre. Br J Surg. 83:1750–1754. 1996. View Article : Google Scholar : PubMed/NCBI

2 

Anderson JN Jr, Beenken SW, Crowe R, Soong SJ, Peters G, Maddox WA and Urist MM: Prognostic factors in minor salivary gland cancer. Head Neck. 17:480–486. 1995. View Article : Google Scholar : PubMed/NCBI

3 

Van der Wal JE, Becking AG, Snow GB and van der Waal I: Distant metastases of adenoid cystic carcinoma of the salivary glands and the value of diagnostic examinations during follow-up. Head Neck. 24:779–783. 2002.PubMed/NCBI

4 

Ramer N, Wu H, Sabo E, Ramer Y, Emanuel P, Orta L and Burstein DE: Prognostic value of quantitative p63 immuno- staining in adenoid cystic carcinoma of salivary gland assessed by computerized image analysis. Cancer. 116:77–83. 2010.PubMed/NCBI

5 

Van der Wal JE, Snow GB and van der Waal I: Intraoral adenoid cystic carcinoma. The presence of perineural spread in relation to site, size, local extension, and metastatic spread in 22 cases. Cancer. 66:2031–2033. 1990.PubMed/NCBI

6 

Vrielinck L, Ostyn F, van Damme B, van den Boqaert W and Fossion E: The significance of perineural spread in adenoid cystic carcinoma of the major and minor salivary glands. Int J Oral Maxillofac Surg. 17:190–193. 1988. View Article : Google Scholar : PubMed/NCBI

7 

Newlin HE, Morris CG, Amdur RJ and Mendenhall WM: Neurotropic melanoma of the head and neck with clinical perineural invasion. Am J Clin Oncol. 28:399–402. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Ayala GE, Dai H, Ittmann M, Li R, Powell M, Frolov A, Wheeler TM, Thompson TC and Rowley D: Growth and survival mechanisms associated with perineural invasion in prostate cancer. Cancer Res. 64:6082–6090. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Pour PM, Bell RH and Batra SK: Neural invasion in the staging of pancreatic cancer. Pancreas. 26:322–325. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Faqan JJ, Collins B, Barnes L, D'Amico F, Myers EN and Johnson JT: Perineural invasion in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 124:637–640. 1998. View Article : Google Scholar : PubMed/NCBI

11 

Rahima B, Shingaki S, Nagata M and Saito C: Prognostic significance of perineural invasion in oral and oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Radiol Endod. 97:423–431. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Go MJ, Eastman DS and Artavanis-Tsakonas S: Cell proliferation control by Notch signaling in Drosophila development. Development. 125:2031–2040. 1998.PubMed/NCBI

13 

Shelly LL, Fuchs C and Miele L: Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds. J Cell Biochem. 73:164–175. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Bigas A, Martin DI and Milner LA: Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol. 18:2324–2333. 1998.PubMed/NCBI

15 

Mumm JS and Kopan R: Notch signaling: from the outside in. Dev Biol. 228:151–165. 2000. View Article : Google Scholar : PubMed/NCBI

16 

Stockhausen MT, Sjölund J and Axelson H: Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells. Exp Cell Res. 310:218–228. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Yoon JH, Kim SA, Kwon SM, Park JH, Park HS, Kim YC, Yoon JH and Ahn SG: 5′-Nitro-indirubinoxime induces G1 cell cycle arrest and apoptosis in salivary gland adenocarcinoma cells through the inhibition of Notch-1 signaling. Biochim Biophys Acta. 1800:352–358. 2010.

18 

Yao J, Duan L, Fan M, Yuan J and Wu X: Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells: involvement of nuclear factor kappa B inhibition. Int J Gynecol Cancer. 17:502–510. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Duan L, Yao J, Wu X and Fan M: Growth suppression induced by Notch1 activation involves Wnt-β-catenin down-regulation in human tongue carcinoma cells. Biol Cell. 98:479–490. 2006.PubMed/NCBI

20 

Leethanakul C, Patel V, Gillespie J, Pallente M, Ensley JF, Koontongkaew S, Liotta LA, Emmert-Buck M and Gutkind JS: Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays. Oncogene. 19:3220–3224. 2000. View Article : Google Scholar : PubMed/NCBI

21 

Nefedova Y, Sullivan DM, Bolick SC, Dalton WS and Gabrilovich DI: Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 111:2220–2229. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Zang S, Chen F, Dai J, Guo D, Tse W, Qu X, Ma D and Ji C: RNAi-mediated knockdown of Notch-1 leads to cell growth inhibition and enhanced chemosensitivity in human breast cancer. Oncol Rep. 23:893–899. 2010.PubMed/NCBI

23 

Gu F, Ma Y, Zhang Z, Zhao J, Kobayashi H, Zhang L and Fu L: Expression of Stat3 and Notch1 is associated with cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 23:671–676. 2010.PubMed/NCBI

24 

Ding LC, She L, Zheng DL, Huang QL, Wang JF, Zheng FF and Lu YG: Notch-4 contributes to the metastasis of salivary adenoid cystic carcinoma. Oncol Rep. 24:363–368. 2010.PubMed/NCBI

25 

Chen W, Zhang HL, Shao XJ, Jiang YG, Zhao XG, Gao X, Li JH, Yang J, Zhang YF, Liu BL and Sun MY: Gene expression profile of salivary adenoid cystic carcinoma associated with perineural invasion. Tohoku J Exp Med. 212:319–334. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Guan XF, Qiu WL, He RG and Zhou XJ: Selection of adenoid cystic carcinoma cell clone highly metastatic to the lung: an experimental study. Int J Oral Maxillofac Surg. 26:116–119. 1997. View Article : Google Scholar : PubMed/NCBI

27 

Tuschl T: Expanding small RNA interference. Nat Biotechnol. 20:446–448. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS and Khvorova A: Rational siRNA design for RNA interference. Nat Biotechnol. 22:326–330. 2004. View Article : Google Scholar : PubMed/NCBI

29 

Wang L, Sun M, Jiang Y, Yang L, Lei D, Lu C, Zhao Y, Zhang P, Yang Y and Li J: Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg. 64:636–641. 2006. View Article : Google Scholar

30 

Chen W, Zhang HL, Jiang YG, Li JH, Liu BL and Sun MY: Inhibition of CD146 gene expression via RNA interference reduces in vitro perineural invasion on ACC-M cell. J Oral Pathol Med. 38:198–205. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Mohr OL: Character changes caused by mutation of an entire region of a chromosome in Drosophila. Genetics. 4:275–282. 1919.PubMed/NCBI

32 

Miele L and Osborne B: Arbiter of differentiation and death: Notch signaling meets apoptosis. J Cell Physiol. 181:393–409. 1999. View Article : Google Scholar : PubMed/NCBI

33 

Cheng P and Gabrilovich D: Notch signaling in differentiation and function of dendritic cells. Immunol Res. 41:1–14. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Baker NE: Notch signaling in the nervous system. Pieces still missing from the puzzle. Bioessays. 22:264–273. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: cell fate control and signal integration in development. Science. 284:770–776. 1999. View Article : Google Scholar : PubMed/NCBI

36 

Milner LA and Bigas A: Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. Blood. 93:2431–2448. 1999.PubMed/NCBI

37 

Kopan R and Ilagan MX: The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 137:216–233. 2009. View Article : Google Scholar : PubMed/NCBI

38 

Clementz AG, Rogowski A, Pandya K, Miele L and Osipo C: Notch-1 and Notch-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications. Breast Cancer Res. 13:R632011. View Article : Google Scholar : PubMed/NCBI

39 

Zamore PD, Tuschl T, Sharp PA and Bartel DP: RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell. 101:25–33. 2000. View Article : Google Scholar : PubMed/NCBI

40 

Yamamoto T, Miyoshi H, Yamamoto N, Yamamoto N, Inoue J and Tsunetsugu-Yokota Y: Lentivirus vectors expressing short hairpin RNAs against the U3-overlapping region of HIV nef inhibit HIV replication and infectivity in primary macrophages. Blood. 108:3305–3312. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Desclaux M, Teigell M, Amar L, Vogel R, Gimenez Y, Ribotta M, Privat A and Mallet J: A novel and efficient gene transfer strategy reduces glial reactivity and improves neuronal survival and axonal growth in vitro. PLoS One. 4:e62272009. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Chen W, Zhang H, Wang J, Cao G, Dong Z, Su H, Zhou X and Zhang S: Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells. Oncol Rep 29: 1797-1804, 2013.
APA
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H. ... Zhang, S. (2013). Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells. Oncology Reports, 29, 1797-1804. https://doi.org/10.3892/or.2013.2317
MLA
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H., Zhou, X., Zhang, S."Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells". Oncology Reports 29.5 (2013): 1797-1804.
Chicago
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H., Zhou, X., Zhang, S."Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells". Oncology Reports 29, no. 5 (2013): 1797-1804. https://doi.org/10.3892/or.2013.2317
Copy and paste a formatted citation
x
Spandidos Publications style
Chen W, Zhang H, Wang J, Cao G, Dong Z, Su H, Zhou X and Zhang S: Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells. Oncol Rep 29: 1797-1804, 2013.
APA
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H. ... Zhang, S. (2013). Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells. Oncology Reports, 29, 1797-1804. https://doi.org/10.3892/or.2013.2317
MLA
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H., Zhou, X., Zhang, S."Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells". Oncology Reports 29.5 (2013): 1797-1804.
Chicago
Chen, W., Zhang, H., Wang, J., Cao, G., Dong, Z., Su, H., Zhou, X., Zhang, S."Lentiviral-mediated gene silencing of Notch-4 inhibits in vitro proliferation and perineural invasion of ACC-M cells". Oncology Reports 29, no. 5 (2013): 1797-1804. https://doi.org/10.3892/or.2013.2317
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