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
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
March-2018 Volume 17 Issue 3

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
March-2018 Volume 17 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

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

Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells

  • Authors:
    • Lufang Wang
    • Yanyan Zhao
    • Qiong Wu
    • Yifu Guan
    • Xin Wu
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China, Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, Liaoning 110000, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 4299-4306
    |
    Published online on: January 18, 2018
       https://doi.org/10.3892/mmr.2018.8455
  • 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

Concurrent radio chemotherapy treatment prolongs the survival rate of patients with advanced cervical cancer; however, it has adverse side‑effects. β‑elemene, an active component of the traditional Chinese medicinal herb Curcuma zedoaria, is a promising alternative therapeutic drug for the treatment of advanced cervical cancer. The aim of the present study was to investigate the antitumor effects of β‑elemene in human cervical cancer SiHa cells and to determine its underlying therapeutic molecular mechanisms. Cell viability, cell cycle progression and apoptosis were detected using an MTT assay and flow cytometry analysis. Furthermore, the levels of cell migration and cell invasion were investigated using Transwell and wound healing assays. The expression levels of Cyclin‑dependent kinase inhibitor 2B (P15), Cyclin D1, cellular tumor antigen p53, apoptosis regulator Bcl‑2 (Bcl‑2), apoptosis regulator BAX (Bax), 72 kDa type IV collagenase (MMP‑2), matrix metalloproteinase‑9 (MMP‑9), β‑catenin, transcription factor 7 (TCF7), and Myc proto‑oncogene protein (c‑Myc) were analyzed via western blotting. The results revealed that β‑elemene inhibited the proliferation of SiHa cells in a dose and time‑dependent manner. Administration of β‑elemene induced G1 phase cell‑cycle arrest, as demonstrated by the upregulation of P15 expression and the downregulation of Cyclin D1 expression. Furthermore, the present study revealed that β‑elemene induced apoptosis in SiHa cells by enhancing the expression of p53 and Bax, and suppressing the expression of Bcl‑2. In addition, treatment with β‑elemene inhibited cell migration and invasion via downregulation of MMP‑2 and MMP‑9 expression levels. Western blotting demonstrated that β‑elemene reduced the expression levels of β‑catenin and its downstream target molecule TCF7, thus resulting in reduced levels of their target proteins, including c‑Myc, Cyclin D1, Bax and MMP‑2 in cervical cancer cells. The results of the present study suggested that β‑elemene may inhibit cell proliferation and invasion, in addition to inducing apoptosis, via attenuation of the Wnt/β‑catenin signaling pathway in cervical cancer cells.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Chen W, Zheng R, Zhang S, Zeng H, Xia C, Zuo T, Yang Z, Zou X and He J: Cancer incidence and mortality in China, 2013. Cancer Lett. 401:63–71. 2017. View Article : Google Scholar : PubMed/NCBI

2 

van Leeuwen CM, Oei AL, Chin KWTK, Crezee J, Bel A, Westermann AM, Buist MR, Franken NAP, Stalpers LJA and Kok HP: A short time interval between radiotherapy and hyperthermia reduces in-field recurrence and mortality in women with advanced cervical cancer. Radiat Oncol. 12:752017. View Article : Google Scholar : PubMed/NCBI

3 

Tewari KS, Sill MW, Long HJ III, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 370:734–743. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Wang H, Tao L, Ni T, Gu H, Jin F, Dai X, Feng J, Ding Y, Xiao W, Guo S, et al: Anticancer efficacy of the ethyl acetate extract from the traditional Chinese medicine herb Celastrus orbiculatus against human gastric cancer. J Ethnopharmacol. 205:147–157. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Kumar D, Basu S, Parija L, Rout D, Manna S, Dandapat J and Debata PR: Curcumin and Ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells. Biomed Pharmacoth. 81:31–37. 2016. View Article : Google Scholar

6 

Xu QY: The clinical value of local application of compound zedoary turmeric oil suppository for cervical human papilloma virus infection. Med Inform. 2:337–338. 2015.(In Chinese).

7 

Zhang X, Zhang Y and Li Y: β-elemene decreases cell invasion by upregulating E-cadherin expression in MCF-7 human breast cancer cells. Oncol Rep. 30:745–750. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Bao F, Qiu J and Zhang H: Potential role of β-elemene on histone H1 in the H22 ascites hepatoma cell line. Mol Med Rep. 6:185–190. 2012.PubMed/NCBI

9 

Wang G, Li X, Huang F, Zhao J, Ding H, Cunningham C, Coad JE, Flynn DC, Reed E and Li QQ: Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci. 62:881–893. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Yao YQ, Ding X, Jia YC, Huang CX, Wang YZ and Xu YH: Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett. 264:127–134. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Liang D, Yang M, Guo B, Yang L, Cao J and Zhang X: HIF-1α induced by β-elemene protects human osteosarcoma cells from undergoing apoptosis. J Cancer Res Clin Oncol. 138:1865–1877. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Polakis P: Wnt signaling and cancer. Genes Dev. 14:1837–1851. 2000.PubMed/NCBI

13 

Chen C, Zhao M, Tian A, Zhang X, Yao Z and Ma X: Aberrant activation of Wnt/β-catenin signaling drives proliferation of bone sarcoma cells. Oncotarget. 6:17570–17583. 2015.PubMed/NCBI

14 

Lu JJ, Dang YY, Huang M, Xu WS, Chen XP and Wang YT: Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae. J Ethnopharmacol. 143:406–411. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Li QQ, Wang G, Huang F, Banda M and Reed E: Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumor cells. J Pharm Pharmacol. 62:1018–1027. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Zhao YS, Zhu TZ, Chen YW, Yao YQ, Wu CM, Wei ZQ, Wang W and Xu YH: β-elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells. J Neurooncol. 107:307–314. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Li CL, Chang L, Guo L, Zhao D, Liu HB, Wang QS, Zhang P, Du WZ, Liu X, Zhang HT, et al: β-elemene induces caspase-dependent apoptosis in human glioma cells in vitro through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Asian Pac J Cancer Prev. 15:10407–10412. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Zhu T, Zhao Y, Zhang J, Li L, Zou L, Yao Y and Xu Y: β-elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. Int J Oncol. 38:419–426. 2011.PubMed/NCBI

19 

Jares P, Colomera D and Campo E: Genetic and molecular pathogenesis of mantle cell lymphoma: Perspectives for new targeted therapeutics. Nat Rev Cancer. 7:750–762. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Diehl JA: Cycling to cancer with cyclin D1. Cancer Biol Ther. 1:226–231. 2002. View Article : Google Scholar : PubMed/NCBI

21 

Guo Q, Dong B, Nan F, Guan D and Zhang Y: 5-Aminolevulinic acid photodynamic therapy in human cervical cancer via the activation of microRNA-143 and suppression of the Bcl-2/Bax signaling pathway. Mol Med Rep. 14:544–550. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Levine AJ and Oren M: The first 30 years of p53: Growing ever more complex. Nat Rev Cancer. 9:749–758. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Yan Y, Liang H, Li T, Li M, Li R, Qin X and Li S: The MMP-1, MMP-2, and MMP-9 gene polymorphisms and susceptibilityto bladder cancer: A meta-analysis. Tumour Biol. 35:3047–3052. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Zhao H, Yuan X, Jiang J, Wang P, Sun X, Wang D and Zheng Q: Antimetastatic effects of licochalcone B on human bladder carcinoma T24 by inhibition of matrix metalloproteinases9 and NF-κB activity. Basic Clin Pharmacol Toxicol. 115:527–533. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R and Kemler R: Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 336:1549–1554. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Valenta T, Hausmann G and Basler K: The many faces and functions of β-catenin. EMBO J. 31:2714–2736. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Koff JL, Ramachandiran S and Bernal-Mizrachi L: A time to kill: Targeting apoptosis in cancer. Int J Mol Sci. 16:2942–2955. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Wu K, Ma L and Zhu J: miR-483-5p promotes growth, invasion and self-renewal of gastric cancer stem cells by Wnt/β-catenin signaling. Mol Med Rep. 14:3421–3428. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Rother K, Johne C, Spiesbach K, Haugwitz U, Tschöp K, Wasner M, Klein-Hitpass L, Möröy T, Mössner J and Engeland K: Identification of Tcf-4 as a transcriptional target of p53 signalling. Oncogene. 23:3376–3384. 2004. View Article : Google Scholar : PubMed/NCBI

31 

Wang J, Shou J and Chen X: Dickkopf-1, an inhibitor of the Wnt signaling pathway, is induced by p53. Oncogene. 30:1843–1848. 2000. View Article : Google Scholar

32 

Kim NH, Kim HS, Kim NG, Lee I, Choi HS, Li XY, Kang SE, Cha SY, Ryu JK, Na JM, et al: p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal. 4:ra712011. View Article : Google Scholar : PubMed/NCBI

33 

Li L, Xu L, Qu X, Zhao M, Yu P, Kang J, Liu Y and Hu X: Cbl-regulated Akt and ERK signals are involved in β-elemene-induced cell apoptosis in lung cancer cells. Mol Med Rep. 4:1243–1246. 2011.PubMed/NCBI

34 

Wu B, Crampton SP and Hughes CC: Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity. 26:227–239. 2007. View Article : Google Scholar : PubMed/NCBI

35 

Imai K, Yokohama Y, Nakanishi I, Ohuchi E, Fujii Y, Nakai N and Okada Y: Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. J Biol Chem. 270:6691–6697. 1995. View Article : Google Scholar : PubMed/NCBI

36 

Zhang X, Li Y, Zhang Y, Song J, Wang Q, Zheng L and Liu D: Beta-elemene blocks epithelial-mesenchymal transition in human breastcancer cell line MCF-7 through Smad3-mediated down-regulation of nuclear transcription factors. PLoS One. 8:e587192013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wang L, Zhao Y, Wu Q, Guan Y and Wu X: Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells. Mol Med Rep 17: 4299-4306, 2018.
APA
Wang, L., Zhao, Y., Wu, Q., Guan, Y., & Wu, X. (2018). Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells. Molecular Medicine Reports, 17, 4299-4306. https://doi.org/10.3892/mmr.2018.8455
MLA
Wang, L., Zhao, Y., Wu, Q., Guan, Y., Wu, X."Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells". Molecular Medicine Reports 17.3 (2018): 4299-4306.
Chicago
Wang, L., Zhao, Y., Wu, Q., Guan, Y., Wu, X."Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells". Molecular Medicine Reports 17, no. 3 (2018): 4299-4306. https://doi.org/10.3892/mmr.2018.8455
Copy and paste a formatted citation
x
Spandidos Publications style
Wang L, Zhao Y, Wu Q, Guan Y and Wu X: Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells. Mol Med Rep 17: 4299-4306, 2018.
APA
Wang, L., Zhao, Y., Wu, Q., Guan, Y., & Wu, X. (2018). Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells. Molecular Medicine Reports, 17, 4299-4306. https://doi.org/10.3892/mmr.2018.8455
MLA
Wang, L., Zhao, Y., Wu, Q., Guan, Y., Wu, X."Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells". Molecular Medicine Reports 17.3 (2018): 4299-4306.
Chicago
Wang, L., Zhao, Y., Wu, Q., Guan, Y., Wu, X."Therapeutic effects of β-elemene via attenuation of the Wnt/β-catenin signaling pathway in cervical cancer cells". Molecular Medicine Reports 17, no. 3 (2018): 4299-4306. https://doi.org/10.3892/mmr.2018.8455
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