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 Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
September-2018 Volume 16 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
September-2018 Volume 16 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

Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma

  • Authors:
    • Bin Xu
    • Qu Chen
    • Cuihua Yue
    • Lei Lan
    • Jingting Jiang
    • Yueping Shen
    • Binfeng Lu
  • View Affiliations / Copyright

    Affiliations: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Epidemiology and Biostatistics, School of Public Health, Soochow University, Suzhou, Jiangsu 215123, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2935-2948
    |
    Published online on: June 28, 2018
       https://doi.org/10.3892/ol.2018.9044
  • 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

Previous studies have demonstrated that the interleukin (IL)‑6/ IL‑6 receptor (IL‑6R) signaling pathway contributes to the pathogenesis of lung cancer. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major pathological subtypes of non‑small cell lung cancer (NSCLC). The present study aimed to elucidate the potential clinical prognosis and biological function of IL‑6R mRNA expression in LUAD and LUSC. The search term ‘lung cancer’ was used to search through the Gene Expression Omnibus database. Including LUAD and LUSC datasets in The Cancer Genome Atlas database, a total of 8 LUAD and 6 LUSC datasets were included in the present analysis. It was observed that a higher expression level of IL‑6R mRNA in tumor tissues was a significant positive prognostic factor for overall survival in LUAD [pooled hazard ratio (HR), 0.48 and P<0.001 for univariate analysis; pooled HR, 0.50 and P<0.001 for multivariate analysis] while there was no similar association in LUSC (pooled HR, 1.59 and P=0.062 for univariate analysis; pooled HR, 1.58 and P=0.079 for multivariate analysis). Correlation analysis revealed that IL‑6 and IL‑6R were negatively correlated in LUAD and positively correlated in LUSC. IL‑6R and its most correlated genes were primarily involved in cell cycle progression in LUAD and primarily involved in tumor angiogenesis, invasion and metastasis in LUSC. These results suggest a possible role of tumoral expression for IL‑6R in LUAD, which means it may have potential as a prognostic marker for this type of cancer.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Torre LA, Siegel RL and Jemal A: Lung cancer statistics. Adv Exp Med Biol. 893:1–19. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Johnson DH, Schiller JH and Bunn PA Jr: Recent clinical advances in lung cancer management. J Clin Oncol. 32:973–982. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, et al: International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6:244–285. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Zhan C, Yan L, Wang L, Sun Y, Wang X, Lin Z, Zhang Y, Shi Y, Jiang W and Wang Q: Identification of immunohistochemical markers for distinguishing lung adenocarcinoma from squamous cell carcinoma. J Thorac Dis. 7:1398–1405. 2015.PubMed/NCBI

7 

Kishimoto T, Akira S, Narazaki M and Taga T: Interleukin-6 family of cytokines and gp130. Blood. 86:1243–1254. 1995.PubMed/NCBI

8 

Hodge DR, Hurt EM and Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 41:2502–2512. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Haura EB, Livingston S and Coppola D: Autocrine interleukin-6/interleukin-6 receptor stimulation in non-small-cell lung cancer. Clin Lung Cancer. 7:273–275. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Yanagawa H, Sone S, Takahashi Y, Haku T, Yano S, Shinohara T and Ogura T: Serum levels of interleukin 6 in patients with lung cancer. Br J Cancer. 71:1095–1098. 1995. View Article : Google Scholar : PubMed/NCBI

11 

Songür N, Kuru B, Kalkan F, Ozdilekcan C, Cakmak H and Hizel N: Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer. Tumori. 90:196–200. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Chang CH, Hsiao CF, Yeh YM, Chang GC, Tsai YH, Chen YM, Huang MS, Chen HL, Li YJ, Yang PC, et al: Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer. 132:1977–1985. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Seike T, Fujita K, Yamakawa Y, Kido MA, Takiguchi S, Teramoto N, Iguchi H and Noda M: Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin Exp Metastasis. 28:13–25. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Noda M, Yamakawa Y, Matsunaga N, Naoe S, Jodoi T, Yamafuji M, Akimoto N, Teramoto N, Fujita K, Ohdo S and Iguchi H: IL-6 receptor is a possible target against growth of metastasized lung tumor cells in the brain. Int J Mol Sci. 14:515–526. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Yi H, Cho HJ, Cho SM, Jo K, Park JA, Kim NH, Amidon GL, Kim JS and Shin HC: Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells. Int J Oncol. 41:310–316. 2012.PubMed/NCBI

16 

Kim NH, Kim SK, Kim DS, Zhang D, Park JA, Yi H, Kim JS and Shin HC: Anti-proliferative action of IL-6R-targeted antibody tocilizumab for non-small cell lung cancer cells. Oncol Lett. 9:2283–2288. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Ando K, Takahashi F, Motojima S, Nakashima K, Kaneko N, Hoshi K and Takahashi K: Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J Clin Oncol. 31:e69–e72. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Ando K, Takahashi F, Kato M, Kaneko N, Doi T, Ohe Y, Koizumi F, Nishio K and Takahashi K: Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer. PLoS One. 9:e1024362014. View Article : Google Scholar : PubMed/NCBI

19 

Stang A: Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 25:603–605. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Budczies J, Klauschen F, Sinn BV, Győrffy B, Schmitt WD, Darb-Esfahani S and Denkert C: Cutoff Finder: A comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One. 7:e518622012. View Article : Google Scholar : PubMed/NCBI

21 

Zhu CQ, Ding K, Strumpf D, Weir BA, Meyerson M, Pennell N, Thomas RK, Naoki K, Ladd-Acosta C, Liu N, et al: Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol. 28:4417–4424. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Rousseaux S, Debernardi A, Jacquiau B, Vitte AL, Vesin A, Nagy-Mignotte H, Moro-Sibilot D, Brichon PY, Lantuejoul S, Hainaut P, et al: Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med. 5:186ra662013. View Article : Google Scholar : PubMed/NCBI

23 

Botling J, Edlund K, Lohr M, Hellwig B, Holmberg L, Lambe M, Berglund A, Ekman S, Bergqvist M, Pontén F, et al: Biomarker discovery in non-small cell lung cancer: Integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin Cancer Res. 19:194–204. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Tang H, Xiao G, Behrens C, Schiller J, Allen J, Chow CW, Suraokar M, Corvalan A, Mao J, White MA, et al: A 12-gene set predicts survival benefits from adjuvant chemotherapy in non-small cell lung cancer patients. Clin Cancer Res. 19:1577–1586. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Der SD, Sykes J, Pintilie M, Zhu CQ, Strumpf D, Liu N, Jurisica I, Shepherd FA and Tsao MS: Validation of a histology-independent prognostic gene signature for early-stage, non-small-cell lung cancer including stage IA patients. J Thorac Oncol. 9:59–64. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Director's Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma, . Shedden K, Taylor JM, Enkemann SA, Tsao MS, Yeatman TJ, Gerald WL, Eschrich S, Jurisica I, Giordano TJ, et al: Gene expression-based survival prediction in lung adenocarcinoma: A multi-site, blinded validation study. Nat Med. 14:822–827. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, et al: Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 8:816–824. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Yu H and Jove R: The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI

29 

Han X, Li F, Fang Z, Gao Y, Li F, Fang R, Yao S, Sun Y, Li L, Zhang W, et al: Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma. Nat Commun. 5:32612014. View Article : Google Scholar : PubMed/NCBI

30 

Sutherland KD and Berns A: Cell of origin of lung cancer. Mol Oncol. 4:397–403. 2010. View Article : Google Scholar : PubMed/NCBI

31 

Hassan KA, Chen G, Kalemkerian GP, Wicha MS and Beer DG: An embryonic stem cell-like signature identifies poorly differentiated lung adenocarcinoma but not squamous cell carcinoma. Clin Cancer Res. 15:6386–6390. 2009. View Article : Google Scholar : PubMed/NCBI

32 

Li P, Zhang L, Yu X, Tong R, Di X, Mao Y, Gao Y, Zhang K, Feng L and Cheng S: Proliferation genes in lung development associated with the prognosis of lung adenocarcinoma but not squamous cell carcinoma. Cancer Sci. 109:308–316. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Montero-Julian FA: The soluble IL-6 receptors: Serum levels and biological function. Cell Mol Biol (Noisy-le-grand). 47:583–597. 2001.PubMed/NCBI

34 

Brooks GD, McLeod L, Alhayyani S, Miller A, Russell PA, Ferlin W, Rose-John S, Ruwanpura S and Jenkins BJ: IL6 trans-signaling promotes KRAS-driven lung carcinogenesis. Cancer Res. 76:866–876. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Balabko L, Andreev K, Burmann N, Schubert M, Mathews M, Trufa DI, Reppert S, Rau T, Schicht M, Sirbu H, et al: Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorγT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung. Sci Rep. 4:73962014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Xu B, Chen Q, Yue C, Lan L, Jiang J, Shen Y and Lu B: Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma. Oncol Lett 16: 2935-2948, 2018.
APA
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., & Lu, B. (2018). Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma. Oncology Letters, 16, 2935-2948. https://doi.org/10.3892/ol.2018.9044
MLA
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., Lu, B."Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma". Oncology Letters 16.3 (2018): 2935-2948.
Chicago
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., Lu, B."Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma". Oncology Letters 16, no. 3 (2018): 2935-2948. https://doi.org/10.3892/ol.2018.9044
Copy and paste a formatted citation
x
Spandidos Publications style
Xu B, Chen Q, Yue C, Lan L, Jiang J, Shen Y and Lu B: Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma. Oncol Lett 16: 2935-2948, 2018.
APA
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., & Lu, B. (2018). Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma. Oncology Letters, 16, 2935-2948. https://doi.org/10.3892/ol.2018.9044
MLA
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., Lu, B."Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma". Oncology Letters 16.3 (2018): 2935-2948.
Chicago
Xu, B., Chen, Q., Yue, C., Lan, L., Jiang, J., Shen, Y., Lu, B."Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma". Oncology Letters 16, no. 3 (2018): 2935-2948. https://doi.org/10.3892/ol.2018.9044
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