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 Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
March-2015 Volume 46 Issue 3

Full Size Image

Cover Legend PDF

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
March-2015 Volume 46 Issue 3

Full Size Image

Cover Legend PDF

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

Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma

  • Authors:
    • Tri Budi Hartomo
    • Thi Van Huyen Pham
    • Nobuyuki Yamamoto
    • Satoshi Hirase
    • Daiichiro Hasegawa
    • Yoshiyuki Kosaka
    • Masafumi Matsuo
    • Akira Hayakawa
    • Yasuhiro Takeshima
    • Kazumoto Iijima
    • Hisahide Nishio
    • Noriyuki Nishimura
  • View Affiliations / Copyright

    Affiliations: Department of Epidemiology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, Department of Hematology and Oncology, Kobe Children's Hospital, Kobe 654-0081, Japan, Department of Medical Rehabilitation, Kobe Gakuin University, Kobe 651-2180, Japan
  • Pages: 1089-1098
    |
    Published online on: December 17, 2014
       https://doi.org/10.3892/ijo.2014.2801
  • 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

Despite the introduction of 13-cis-retinoic acid (13-cis-RA) into the current chemotherapy, more than half of high-risk neuroblastoma patients have experienced tumor relapses driven by chemoresistant cancer stem cells (CSCs) that can be isolated by their ability to grow as spheres. Although aldehyde dehydrogenase (ALDH) has been used to characterize CSCs in certain cancers, ALDH remains elusive in neuroblastoma. In the present study, we determined ALDH activity and expression of its 19 isoforms in spheres and parental cells of neuroblastoma. ALDH activity and several ALDH isoforms were consistently induced in spheres of different neuroblastoma cells. While ALDH1A2, ALDH1L1 and ALDH3B2 expression was consistently induced in spheres and associated with the sphere and colony formation, only ALDH1A2 expression was significantly correlated with the poor prognosis of neuroblastoma patients. ALDH1A2 expression was further associated with the growth and undifferentiation of neuroblastoma xenografts and the resistance of neuroblastoma cells to 13-cis-RA. These results suggest that ALDH1A2 is involved in the regulation of CSC properties in neuroblastoma.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Laverdière C, Liu Q, Yasui Y, et al: Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 101:1131–1140. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362:2202–2211. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Cole KA and Maris JM: New strategies in refractory and recurrent neuroblastoma: translational opportunities to impact patient outcome. Clin Cancer Res. 18:2423–2428. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 341:1165–1173. 1999. View Article : Google Scholar : PubMed/NCBI

6 

Yu AL, Gilman AL, Ozkaynak MF, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 363:1324–1334. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 8:755–768. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Vermeulen L, de Sousa e Melo F, Richel DJ and Medema JP: The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncol. 13:e83–e89. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Cheung N-KV and Dyer MA: Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 13:397–411. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Hansford LM, McKee AE, Zhang L, et al: Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res. 67:11234–11243. 2007. View Article : Google Scholar : PubMed/NCBI

11 

Hirschmann-Jax C, Foster AE, Wulf GG, et al: A distinct ‘side population’ of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 101:14228–14233. 2004. View Article : Google Scholar

12 

Takenobu H, Shimozato O, Nakamura T, et al: CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene. 30:97–105. 2011. View Article : Google Scholar

13 

Hsu DM, Agarwal S, Benham A, et al: G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic. Cancer Res. 73:4134–4146. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Sartelet H, Imbriglio T, Nyalendo C, et al: CD133 expression is associated with poor outcome in neuroblastoma via chemo-resistance mediated by the AKT pathway. Histopathology. 60:1144–1155. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Jackson B, Brocker C, Thompson DC, et al: Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 5:283–303. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Kastan MB, Schlaffer E, Russo JE, Colvin OM, Civin CI and Hilton J: Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood. 75:1947–1950. 1990.PubMed/NCBI

17 

Ma I and Allan AL: The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 7:292–306. 2011. View Article : Google Scholar

18 

Marcato P, Dean CA, Giacomantonio CA and Lee PWK: Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle. 10:1378–1384. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Sullivan JP, Spinola M, Dodge M, et al: Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res. 70:9937–9948. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Chen Y, Orlicky DJ, Matsumoto A, Singh S, Thompson DC and Vasiliou V: Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer. Biochem Biophys Res Commun. 405:173–179. 2011. View Article : Google Scholar : PubMed/NCBI

21 

van den Hoogen C, van der Horst G, Cheung H, et al: High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 70:5163–5173. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Nishimura N, Pham TVH, Hartomo TB, et al: Rab15 expression correlates with retinoic acid-induced differentiation of neuroblastoma cells. Oncol Rep. 26:145–151. 2011.PubMed/NCBI

23 

Pham TVH, Hartomo TB, Lee MJ, et al: Rab15 alternative splicing is altered in spheres of neuroblastoma cells. Oncol Rep. 27:2045–2049. 2012.PubMed/NCBI

24 

Nishimura N, Hartomo TB, Pham TVH, et al: Epigallocatechin gallate inhibits sphere formation of neuroblastoma BE(2)-C cells. Environ Health Prev Med. 17:246–251. 2012. View Article : Google Scholar :

25 

Tomayko MM and Reynolds CP: Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 24:148–154. 1989. View Article : Google Scholar : PubMed/NCBI

26 

Kanda I, Nishimura N, Nakatsuji H, Yamamura R, Nakanishi H and Sasaki T: Involvement of Rab13 and JRAB/MICAL-L2 in epithelial cell scattering. Oncogene. 27:1687–1695. 2008. View Article : Google Scholar

27 

Coulon A, Flahaut M, Mühlethaler-Mottet A, et al: Functional sphere profiling reveals the complexity of neuroblastoma tumor-initiating cell model. Neoplasia. 13:991–1004. 2011.PubMed/NCBI

28 

Niederreither K, Subbarayan V, Dollé P and Chambon P: Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet. 21:444–448. 1999. View Article : Google Scholar : PubMed/NCBI

29 

Deak KL, Dickerson ME, Linney E, et al: Analysis of ALDH1A2, CYP26A1, CYP26B1, CRABP1, and CRABP2 in human neural tube defects suggests a possible association with alleles in ALDH1A2. Birth Defects Res A Clin Mol Teratol. 73:868–875. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Pavan M, Ruiz VF, Silva FA, et al: ALDH1A2 (RALDH2) genetic variation in human congenital heart disease. BMC Med Genet. 10:1132009. View Article : Google Scholar : PubMed/NCBI

31 

Styrkarsdottir U, Thorleifsson G, Helgadottir HT, et al: Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31. Nat Genet. 46:498–502. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Duester G: Retinoic acid synthesis and signaling during early organogenesis. Cell. 134:921–931. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Niederreither K and Dollé P: Retinoic acid in development: towards an integrated view. Nat Rev Genet. 9:541–553. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Patel M, Lu L, Zander DS, Sreerama L, Coco D and Moreb JS: ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors. Lung Cancer. 59:340–349. 2008. View Article : Google Scholar

35 

Kim H, Lapointe J, Kaygusuz G, et al: The retinoic acid synthesis gene ALDH1a2 is a candidate tumor suppressor in prostate cancer. Cancer Res. 65:8118–8124. 2005. View Article : Google Scholar : PubMed/NCBI

36 

Touma SE, Perner S, Rubin MA, Nanus DM and Gudas LJ: Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. Biochem Pharmacol. 78:1127–1138. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Mao P, Joshi K, Li J, et al: Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci USA. 110:8644–8649. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Huang S, Laoukili J, Epping MT, et al: ZNF423 is critically required for retinoic acid-induced differentiation and is a marker of neuroblastoma outcome. Cancer Cell. 15:328–340. 2009. View Article : Google Scholar : PubMed/NCBI

39 

Hölzel M, Huang S, Koster J, et al: NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell. 142:218–229. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Hartomo TB, Van Huyen Pham T, Yamamoto N, Hirase S, Hasegawa D, Kosaka Y, Matsuo M, Hayakawa A, Takeshima Y, Iijima K, Iijima K, et al: Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma. Int J Oncol 46: 1089-1098, 2015.
APA
Hartomo, T.B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y. ... Nishimura, N. (2015). Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma. International Journal of Oncology, 46, 1089-1098. https://doi.org/10.3892/ijo.2014.2801
MLA
Hartomo, T. B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y., Matsuo, M., Hayakawa, A., Takeshima, Y., Iijima, K., Nishio, H., Nishimura, N."Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma". International Journal of Oncology 46.3 (2015): 1089-1098.
Chicago
Hartomo, T. B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y., Matsuo, M., Hayakawa, A., Takeshima, Y., Iijima, K., Nishio, H., Nishimura, N."Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma". International Journal of Oncology 46, no. 3 (2015): 1089-1098. https://doi.org/10.3892/ijo.2014.2801
Copy and paste a formatted citation
x
Spandidos Publications style
Hartomo TB, Van Huyen Pham T, Yamamoto N, Hirase S, Hasegawa D, Kosaka Y, Matsuo M, Hayakawa A, Takeshima Y, Iijima K, Iijima K, et al: Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma. Int J Oncol 46: 1089-1098, 2015.
APA
Hartomo, T.B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y. ... Nishimura, N. (2015). Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma. International Journal of Oncology, 46, 1089-1098. https://doi.org/10.3892/ijo.2014.2801
MLA
Hartomo, T. B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y., Matsuo, M., Hayakawa, A., Takeshima, Y., Iijima, K., Nishio, H., Nishimura, N."Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma". International Journal of Oncology 46.3 (2015): 1089-1098.
Chicago
Hartomo, T. B., Van Huyen Pham, T., Yamamoto, N., Hirase, S., Hasegawa, D., Kosaka, Y., Matsuo, M., Hayakawa, A., Takeshima, Y., Iijima, K., Nishio, H., Nishimura, N."Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma". International Journal of Oncology 46, no. 3 (2015): 1089-1098. https://doi.org/10.3892/ijo.2014.2801
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