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
December-2018 Volume 40 Issue 6

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
December-2018 Volume 40 Issue 6

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

miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3

  • Authors:
    • Yiming Liang
    • Enliang Li
    • Jiaqi Min
    • Chengwu Gong
    • Jun Gao
    • Jiyuan Ai
    • Wenjun Liao
    • Linquan Wu
  • View Affiliations / Copyright

    Affiliations: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of General Surgery, Children's Hospital of Jiangxi Province, Nanchang, Jiangxi 330006, P.R. China
    Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 3261-3272
    |
    Published online on: September 28, 2018
       https://doi.org/10.3892/or.2018.6745
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The interferon-induced transmembrane protein 3 (IFITM3, also called 1‑8U) gene represents dysregulated expression in various tumors and is involved in tumorigenesis and progression. However, the role of IFITM3 and its underlying mechanism in hepatocellular carcinoma (HCC) are still far from elucidated. MicroRNAs (miRNAs), a class of endogenous (approximately 22 nucleotides) small noncoding RNAs, can post‑transcriptionally regulate gene expression by repressing protein translation or silencing the expression of target genes that play critical roles in various cancers. miR‑29a was identified as being aberrantly expressed in a significant proportion of HCC. However, the correlation between IFITM3 and miR‑29a has not been reported to date. In this study, we investigated the expression of IFITM3 in HCC and its effect on the biological behavior of HCC cells as well as the association between IFITM3 and miR‑29a. We determined that IFITM3 was upregulated and miR‑29a downregulated in HCC tissues and that they were associated with HCC tumor size, tumor multifocal, and venous invasion. The expression of IFITM3 in HCC tissues was negatively correlated with miR‑29a expression. Additionally, IFITM3 overexpression and miR‑29a nonoverexpression were related to poor prognosis of HCC patients. Knockdown of IFITM3 inhibited migration, invasion, proliferation and promoted apoptosis of HCC cells, which are consistent with the effects of upregulated miR‑29a. Additionally, after upregulation of IFITM3, the invasion, migration and proliferation abilities of HL‑7702 cells were increased, but the apoptosis rate was decreased. Furthermore, using a Dual‑Luciferase reporter gene assay, we identified IFITM3 as a new functional target gene of miR‑29a. In conclusion, our findings demonstrated that the migration, invasion, proliferation and apoptosis features of HCC cells could be regulated by miR‑29a via IFITM3. Thus, the present study indicated that miR‑29a and IFITM3 play critical roles in the development and progression of HCC, revealing that miR‑29a and IFITM3 may be novel potential therapeutic targets for patients with HCC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

3 

Ochiai T, Ikoma H, Okamoto K, Kokuba Y, Sonoyama T and Otsuji E: Clinicopathologic features and risk factors for extrahepatic recurrences of hepatocellular carcinoma after curative resection. World J Surg. 36:136–143. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Yang Y, Nagano H, Ota H, Morimoto O, Nakamura M, Wada H, Noda T, Damdinsuren B, Marubashi S, Miyamoto A, et al: Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery. 141:196–202. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 389:56–66. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Bailey CC, Zhong G, Huang IC and Farzan M: IFITM-family proteins: The cells first line of antiviral defense. Annu Rev Virol. 1:261–283. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Bailey CC, Kondur HR, Huang IC and Farzan M: Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem. 288:32184–32193. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Feeley EM, Sims JS, John SP, Chin CR, Pertel T, Chen LM, Gaiha GD, Ryan BJ, Donis RO, Elledge SJ and Brass AL: IFITM3 inhibits influenza a virus infection by preventing cytosolic entry. PLoS Pathog. 7:e10023372011. View Article : Google Scholar : PubMed/NCBI

10 

Li D, Peng Z, Tang H, Wei P, Kong X, Yan D, Huang F, Li Q, Le X, Li Q and Xie K: KLF4-mediated negative regulation of IFITM3 expression plays a critical role in colon cancer pathogenesis. Clin Cancer Res. 17:3558–3568. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Andreu P, Colnot S, Godard C, Laurent-Puig P, Lamarque D, Kahn A, Perret C and Romagnolo B: Identification of the IFITM family as a new molecular marker in human colorectal tumors. Cancer Res. 66:1949–1955. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Bing Z, Wang H, Gang Z and Ping L: The role of IFITM3 in the growth and migration of human glioma cells. BMC Neurol. 13:2102013. View Article : Google Scholar : PubMed/NCBI

13 

Place RF, Li LC, Pookot D, Noonan EJ and Dahiya R: MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 105:1608–1613. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Kota J, Chivukula RR, ODonnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, et al: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 137:1005–1017. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Fang Y, Xue JL, Shen Q, Chen J and Tian L: MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 55:1852–1862. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y and Zheng X: miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 275:44–53. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Wong CC, Wong CM, Tung EK, Au SL, Lee JM, Poon RT, Man K and Ng IO: The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology. 140:322–331. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, Qin LX and Wu XZ: microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 30:1321–1326. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Mahati S, Xiao L, Yang Y, Mao R and Bao Y: miR-29a suppresses growth and migration of hepatocellular carcinoma by regulating CLDN1. Biochem Biophys Res Commun. 486:732–737. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Kogure T, Kondo Y, Kakazu E, Ninomiya M, Kimura O and Shimosegawa T: Involvement of miRNA-29a in epigenetic regulation of transforming growth factor-beta-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Hepatol Res. 44:907–919. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Cho HJ, Kim SS, Nam JS, Kim JK, Lee JH, Kim B, Wang HJ, Kim BW, Lee JD, Kang DY, et al: Low levels of circulating microRNA-26a/29a as poor prognostic markers in patients with hepatocellular carcinoma who underwent curative treatment. Clin Res Hepatol Gastroenterol. 41:181–189. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Liu W, Liang B, Liu H, Huang Y, Yin X, Zhou F, Yu X, Feng Q, Li E, Zou Z and Wu L: Overexpression of nonSMC condensin I complex subunit G serves as a promising prognostic marker and therapeutic target for hepatocellular carcinoma. Int J Mol Med. 40:731–738. 2017. View Article : Google Scholar : PubMed/NCBI

25 

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

26 

Li C, Miao R, Liu S, Wan Y, Zhang S, Deng Y, Bi J, Qu K, Zhang J and Liu C: Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis. Oncotarget. 8:28683–28695. 2017.PubMed/NCBI

27 

Yuan R, Wang K, Hu J, Yan C, Li M, Yu X, Liu X, Lei J, Guo W, Wu L, et al: Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying beta-catenin degradation. Cancer Res. 74:5287–5300. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Fabbri M, Calore F, Paone A, Galli R and Calin GA: Epigenetic regulation of miRNAs in cancer. Adv Exp Med Biol. 754:137–148. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Yu G, Chen X, Chen S, Ye W, Hou K and Liang M: miR-19a, miR-122 and miR-223 are differentially regulated by hepatitis B virus X protein and involve in cell proliferation in hepatoma cells. J Transl Med. 14:1222016. View Article : Google Scholar : PubMed/NCBI

30 

Lewin AR, Reid LE, McMahon M, Stark GR and Kerr IM: Molecular analysis of a human interferon-inducible gene family. Eur J Biochem. 199:417–423. 1991. View Article : Google Scholar : PubMed/NCBI

31 

Hu J, Wang S, Zhao Y, Guo Q, Zhang D, Chen J, Li J, Fei Q and Sun Y: Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer. Oncol Rep. 32:2648–2656. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Jia Y, Zhang M, Jiang W, Zhang Z, Huang S and Wang Z: Overexpression of IFITM3 predicts the high risk of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy. PeerJ. 3:e13552015. View Article : Google Scholar : PubMed/NCBI

33 

Yang M, Gao H, Chen P, Jia J and Wu S: Knockdown of interferon-induced transmembrane protein 3 expression suppresses breast cancer cell growth and colony formation and affects the cell cycle. Oncol Rep. 30:171–178. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Meister G: miRNAs get an early start on translational silencing. Cell. 131:25–28. 2007. View Article : Google Scholar : PubMed/NCBI

35 

Chianchiano P, Pezhouh MK, Kim A, Luchini C, Cameron A, Weiss MJ, He J, Voltaggio L, Oshima K, Anders RA and Wood LD: Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations. Hum Pathol. 72:127–134. 2018. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Liang Y, Li E, Min J, Gong C, Gao J, Ai J, Liao W and Wu L: miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3. Oncol Rep 40: 3261-3272, 2018.
APA
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J. ... Wu, L. (2018). miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3. Oncology Reports, 40, 3261-3272. https://doi.org/10.3892/or.2018.6745
MLA
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J., Liao, W., Wu, L."miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3". Oncology Reports 40.6 (2018): 3261-3272.
Chicago
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J., Liao, W., Wu, L."miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3". Oncology Reports 40, no. 6 (2018): 3261-3272. https://doi.org/10.3892/or.2018.6745
Copy and paste a formatted citation
x
Spandidos Publications style
Liang Y, Li E, Min J, Gong C, Gao J, Ai J, Liao W and Wu L: miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3. Oncol Rep 40: 3261-3272, 2018.
APA
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J. ... Wu, L. (2018). miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3. Oncology Reports, 40, 3261-3272. https://doi.org/10.3892/or.2018.6745
MLA
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J., Liao, W., Wu, L."miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3". Oncology Reports 40.6 (2018): 3261-3272.
Chicago
Liang, Y., Li, E., Min, J., Gong, C., Gao, J., Ai, J., Liao, W., Wu, L."miR‑29a suppresses the growth and metastasis of hepatocellular carcinoma through IFITM3". Oncology Reports 40, no. 6 (2018): 3261-3272. https://doi.org/10.3892/or.2018.6745
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