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
2014-March Volume 31 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
2014-March Volume 31 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

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

  • Authors:
    • Kin Tak Chan
    • Mei Yuk Choi
    • Kenneth K.Y. Lai
    • Winnie Tan
    • Lai Nar Tung
    • Ho Yu Lam
    • Daniel K.H. Tong
    • Nikki P. Lee
    • Simon Law
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, The University of Hong Kong, Hong Kong, SAR, P.R. China
  • Pages: 1296-1304
    |
    Published online on: January 16, 2014
       https://doi.org/10.3892/or.2014.2981
  • 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

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in endemic Asian regions. In the present study, we investigated the clinical implication and role of transferrin receptor CD71 in ESCC. CD71 has a physiological role in cellular iron intake and is implicated in the carcinogenesis of various types of tumors. In our cohort, more than a 2-fold upregulation of the CD71 transcript was detected in 61.5% of patients using quantitative polymerase chain reaction. Immunohistochemical analysis also showed strong membranous and cytoplasmic localization of CD71 in paraffin-embedded tumors. Staining parallel tumor sections with the proliferative marker Ki-67 revealed that the pattern of Ki-67 staining was associated with CD71 expression. Analysis of clinicopathological data indicated that CD71 overexpression can be used as an indicator for advanced T4 stage (p=0.0307). These data suggested a strong link between CD71 and ESCC. Subsequent in vitro assays using short interfering RNA (siRNA) to suppress CD71 expression confirmed the tumorigenic properties of CD71 in ESCC; cell growth inhibition and cell cycle arrest at S phase were observed in CD71-suppressed cells. The underlying mechanism involved activation of the MEK/ERK pathway. In summary, the present study provides evidence showing the tumorigenic properties of CD71 in ESCC with clinical correlations and suggests targeting CD71 as a strategy for the treatment of ESCC.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar

2 

Law S, Kwong DL, Kwok KF, et al: Improvement in treatment results and long-term survival of patients with esophageal cancer: impact of chemoradiation and change in treatment strategy. Ann Surg. 238:339–348. 2003.PubMed/NCBI

3 

Law S and Wong J: The current management of esophageal cancer. Adv Surg. 41:93–119. 2007. View Article : Google Scholar

4 

Chen X, Yang G, Ding WY, Bondoc F, Curtis SK and Yang CS: An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis. 20:1801–1808. 1999. View Article : Google Scholar : PubMed/NCBI

5 

Cross AJ, Freedman ND, Ren J, et al: Meat consumption and risk of esophageal and gastric cancer in a large prospective study. Am J Gastroenterol. 106:432–442. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Boult J, Roberts K, Brookes MJ, et al: Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res. 14:379–387. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Desoize B: Metals and metal compounds in cancer treatment. Anticancer Res. 24:1529–1544. 2004.PubMed/NCBI

8 

Sanchez M, Galy B, Dandekar T, et al: Iron regulation and the cell cycle: identification of an iron-responsive element in the 3′-untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy. J Biol Chem. 281:22865–22874. 2006.

9 

Brookes MJ, Boult J, Roberts K, et al: A role for iron in Wnt signalling. Oncogene. 27:966–975. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Song S, Christova T, Perusini S, et al: Wnt inhibitor screen reveals iron dependence of β-catenin signaling in cancers. Cancer Res. 71:7628–7639. 2011.PubMed/NCBI

11 

Munoz P, Zavala G, Castillo K, Aguirre P, Hidalgo C and Nunez MT: Effect of iron on the activation of the MAPK/ERK pathway in PC12 neuroblastoma cells. Biol Res. 39:189–190. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Yu Y and Richardson DR: Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1. J Biol Chem. 286:15413–15427. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Kaomongkolgit R, Cheepsunthorn P, Pavasant P and Sanchavanakit N: Iron increases MMP-9 expression through activation of AP-1 via ERK/Akt pathway in human head and neck squamous carcinoma cells. Oral Oncol. 44:587–594. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Kukulj S, Jaganjac M, Boranic M, Krizanac S, Santic Z and Poljak-Blazi M: Altered iron metabolism, inflammation, transferrin receptors, and ferritin expression in non-small-cell lung cancer. Med Oncol. 27:268–277. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Habashy HO, Powe DG, Staka CM, et al: Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer Res Treat. 119:283–293. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Jiang XP, Elliott RL and Head JF: Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res. 30:759–765. 2010.PubMed/NCBI

17 

Magro G, Cataldo I, Amico P, et al: Aberrant expression of TfR1/CD71 in thyroid carcinomas identifies a novel potential diagnostic marker and therapeutic target. Thyroid. 21:267–277. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Testa U, Pelosi E and Peschle C: The transferrin receptor. Crit Rev Oncog. 4:241–276. 1993.

19 

Aisen P: Transferrin receptor 1. Int J Biochem Cell Biol. 36:2137–2143. 2004. View Article : Google Scholar

20 

Sargent PJ, Farnaud S and Evans RW: Structure/function overview of proteins involved in iron storage and transport. Curr Med Chem. 12:2683–2693. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Prutki M, Poljak-Blazi M, Jakopovic M, Tomas D, Stipancic I and Zarkovic N: Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer. Cancer Lett. 238:188–196. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Wada S, Noguchi T, Takeno S and Kawahara K: PIK3CA and TFRC located in 3q are new prognostic factors in esophageal squamous cell carcinoma. Ann Surg Oncol. 13:961–966. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Hu Y, Lam KY, Wan TS, et al: Establishment and characterization of HKESC-1, a new cancer cell line from human esophageal squamous cell carcinoma. Cancer Genet Cytogenet. 118:112–120. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Hu YC, Lam KY, Law SY, et al: Establishment, characterization, karyotyping, and comparative genomic hybridization analysis of HKESC-2 and HKESC-3: two newly established human esophageal squamous cell carcinoma cell lines. Cancer Genet Cytogenet. 135:120–127. 2002. View Article : Google Scholar

25 

Tang JC, Wan TS, Wong N, et al: Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line SLMT-1 of Chinese origin. Cancer Genet Cytogenet. 124:36–41. 2001. View Article : Google Scholar : PubMed/NCBI

26 

Zhang H, Jin Y, Chen X, et al: Cytogenetic aberrations in immortalization of esophageal epithelial cells. Cancer Genet Cytogenet. 165:25–35. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Hui MK, Chan KW, Luk JM, et al: Cytoplasmic Forkhead Box M1 (FoxM1) in esophageal squamous cell carcinoma significantly correlates with pathological disease stage. World J Surg. 36:90–97. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Hui MK, Lai KK, Chan KW, et al: Prognostic significance of phosphorylated RON in esophageal squamous cell carcinoma. Med Oncol. 29:1699–1706. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Lee NP, Leung KW, Wo JY, Tam PC, Yeung WS and Luk JM: Blockage of testicular connexins induced apoptosis in rat seminiferous epithelium. Apoptosis. 11:1215–1229. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Lee NP, Tsang FH, Shek FH, et al: Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int J Cancer. 127:968–976. 2010.PubMed/NCBI

31 

Chan KT and Lung ML: Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 53:519–526. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Liu LX, Lee NP, Chan VW, et al: Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology. 50:1453–1463. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Hanninen MM, Haapasalo J, Haapasalo H, et al: Expression of iron-related genes in human brain and brain tumors. BMC Neurosci. 10:362009. View Article : Google Scholar : PubMed/NCBI

34 

Ryschich E, Huszty G, Knaebel HP, Hartel M, Buchler MW and Schmidt J: Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas. Eur J Cancer. 40:1418–1422. 2004. View Article : Google Scholar : PubMed/NCBI

35 

Sciot R, Paterson AC, van Eyken P, Callea F, Kew MC and Desmet VJ: Transferrin receptor expression in human hepatocellular carcinoma: an immunohistochemical study of 34 cases. Histopathology. 12:53–63. 1988. View Article : Google Scholar : PubMed/NCBI

36 

Cmejla R, Petrak J and Cmejlova J: A novel iron responsive element in the 3′ UTR of human MRCKα. Biochem Biophys Res Commun. 341:158–166. 2006.

37 

Cmejla R, Ptackova P, Petrak J, et al: Human MRCKα is regulated by cellular iron levels and interferes with transferrin iron uptake. Biochem Biophys Res Commun. 395:163–167. 2010.

38 

Schaar DG, Medina DJ, Moore DF, Strair RK and Ting Y: miR-320 targets transferrin receptor 1 (CD71) and inhibits cell proliferation. Exp Hematol. 37:245–255. 2009. View Article : Google Scholar : PubMed/NCBI

39 

Ford SJ, Obeidy P, Lovejoy DB, et al: Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo. Br J Pharmacol. 168:1316–1328. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Loisel S, Andre PA, Golay J, et al: Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia. Mol Cancer. 10:422011. View Article : Google Scholar

41 

Du H, Yao W, Fang M and Wu D: ARF triggers cell G1 arrest by a P53 independent ERK pathway. Mol Cell Biochem. 357:415–422. 2011. View Article : Google Scholar : PubMed/NCBI

42 

McCubrey JA, Steelman LS, Chappell WH, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar : PubMed/NCBI

43 

Sahu RP, Zhang R, Batra S, Shi Y and Srivastava SK: Benzyl isothiocyanate-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of MAPK in human pancreatic cancer cells. Carcinogenesis. 30:1744–1753. 2009. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Chan KT, Choi MY, Lai KK, Tan W, Tung LN, Lam HY, Tong DK, Lee NP and Law S: Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma. Oncol Rep 31: 1296-1304, 2014.
APA
Chan, K.T., Choi, M.Y., Lai, K.K., Tan, W., Tung, L.N., Lam, H.Y. ... Law, S. (2014). Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma. Oncology Reports, 31, 1296-1304. https://doi.org/10.3892/or.2014.2981
MLA
Chan, K. T., Choi, M. Y., Lai, K. K., Tan, W., Tung, L. N., Lam, H. Y., Tong, D. K., Lee, N. P., Law, S."Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma". Oncology Reports 31.3 (2014): 1296-1304.
Chicago
Chan, K. T., Choi, M. Y., Lai, K. K., Tan, W., Tung, L. N., Lam, H. Y., Tong, D. K., Lee, N. P., Law, S."Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma". Oncology Reports 31, no. 3 (2014): 1296-1304. https://doi.org/10.3892/or.2014.2981
Copy and paste a formatted citation
x
Spandidos Publications style
Chan KT, Choi MY, Lai KK, Tan W, Tung LN, Lam HY, Tong DK, Lee NP and Law S: Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma. Oncol Rep 31: 1296-1304, 2014.
APA
Chan, K.T., Choi, M.Y., Lai, K.K., Tan, W., Tung, L.N., Lam, H.Y. ... Law, S. (2014). Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma. Oncology Reports, 31, 1296-1304. https://doi.org/10.3892/or.2014.2981
MLA
Chan, K. T., Choi, M. Y., Lai, K. K., Tan, W., Tung, L. N., Lam, H. Y., Tong, D. K., Lee, N. P., Law, S."Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma". Oncology Reports 31.3 (2014): 1296-1304.
Chicago
Chan, K. T., Choi, M. Y., Lai, K. K., Tan, W., Tung, L. N., Lam, H. Y., Tong, D. K., Lee, N. P., Law, S."Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma". Oncology Reports 31, no. 3 (2014): 1296-1304. https://doi.org/10.3892/or.2014.2981
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