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
February-2021 Volume 21 Issue 2

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
February-2021 Volume 21 Issue 2

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

  • Supplementary Files
    • Supplementary_Data.pdf
Article Open Access

MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells

  • Authors:
    • Zhi-Qiang Ye
    • Han-Bin Chen
    • Tai-Yu Zhang
    • Zhi Chen
    • Ling Tian
    • Dian-Na Gu
  • View Affiliations / Copyright

    Affiliations: Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Chemoradiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, P.R. China, Department of Chemoradiotherapy, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China
    Copyright: © Ye et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 139
    |
    Published online on: December 20, 2020
       https://doi.org/10.3892/ol.2020.12400
  • 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

Senescence is activated in response to gemcitabine to prevent the propagation of cancer cells. However, there is little evidence on whether senescence is involved in gemcitabine resistance in pancreatic cancer. Increasing evidence has demonstrated that microRNAs (miRs) are potential regulators of cellular senescence. The present study aimed to investigate whether aberrant miR‑7 expression modulated senescence to influence pancreatic cancer resistance to chemotherapy. In the present study, cell senescence assay, ALDEFLUOR™ assay, luciferase reporter assay, flow cytometry, quantitative PCR, immunohistochemistry and western blot analysis were performed to explore the association between senescence and gemcitabine therapy response, and to clarify the underlying mechanisms. The present study revealed that gemcitabine‑induced chronically existing senescent pancreatic cells possessed stemness markers. Therapy‑induced senescence led to gemcitabine resistance. Additionally, it was found that miR‑7 expression was decreased in gemcitabine‑resistant pancreatic cancer cells, and that miR‑7 acted as an important regulator of cellular senescence by targeting poly (ADP‑ribose) polymerase 1 (PARP1)/NF‑κB signaling. When miR‑7 expression was restored, it was able to sensitize pancreatic cancer cells to gemcitabine. In conclusion, the present study demonstrated that miR‑7 regulated cellular senescence and relieved gemcitabine resistance by targeting the PARP1/NF‑κB axis in pancreatic cancer cells.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI

2 

Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W and Palmer DH: Therapeutic developments in pancreatic cancer: Current and future perspectives. Nat Rev Gastroenterol Hepatol. 15:333–348. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Mohammed S, Van Buren G II and Fisher WE: Pancreatic cancer: Advances in treatment. World J Gastroenterol. 20:9354–9360. 2014.PubMed/NCBI

4 

Marino Gammazza A, Campanella C, Barone R, Caruso Bavisotto C, Gorska M, Wozniak M, Carini F, Cappello F, D'Anneo A, Lauricella M, et al: Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence. Cancer Lett. 385:75–86. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Li W, Wang W, Dong H, Li Y, Li L, Han L, Han Z, Wang S, Ma D and Wang H: Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78. Oncol Rep. 31:2525–2534. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Lee JJ, Park IH, Rhee WJ, Kim HS and Shin JS: HMGB1 modulates the balance between senescence and apoptosis in response to genotoxic stress. FASEB J. 33:10942–10953. 2019. View Article : Google Scholar : PubMed/NCBI

7 

Perez-Mancera PA, Young AR and Narita M: Inside and out: The activities of senescence in cancer. Nat Rev Cancer. 14:547–558. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Dorr JR, Yu Y, Milanovic M, Beuster G, Zasada C, Däbritz JH, Lisec J, Lenze D, Gerhardt A, Schleicher K, et al: Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature. 501:421–425. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH III, Dang VM, Appleton J, O'Connell MP, Cheng P, et al: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 532:250–254. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Sun Y, Coppe JP and Lam EW: Cellular senescence: The sought or the unwanted? Trends Mol Med. 24:871–885. 2018. View Article : Google Scholar : PubMed/NCBI

11 

Song Y, Baba T and Mukaida N: Gemcitabine induces cell senescence in human pancreatic cancer cell lines. Biochem Biophys Res Commun. 477:515–519. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Hua YQ, Zhu YD, Xie GQ, Zhang K, Sheng J, Zhu ZF, Ning ZY, Chen H, Chen Z, Meng ZQ and Liu LM: Long non-coding SBF2-AS1 acting as a competing endogenous RNA to sponge microRNA-142-3p to participate in gemcitabine resistance in pancreatic cancer via upregulating TWF1. Aging (Albany NY). 11:8860–8878. 2019. View Article : Google Scholar : PubMed/NCBI

13 

Williams J, Smith F, Kumar S, Vijayan M and Reddy PH: Are microRNAs true sensors of ageing and cellular senescence? Ageing Res Rev. 35:350–363. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Gu DN, Jiang MJ, Mei Z, Dai JJ, Dai CY, Fang C, Huang Q and Tian L: microRNA-7 impairs autophagy-derived pools of glucose to suppress pancreatic cancer progression. Cancer Lett. 400:69–78. 2017. View Article : Google Scholar : PubMed/NCBI

15 

Luo H, Liang H, Chen Y, Chen S, Xu Y, Xu L, Liu J, Zhou K, Peng J, Guo G, et al: miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone. Chem Biol Interact. 283:84–90. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Lai J, Yang H, Zhu Y, Ruan M, Huang Y and Zhang Q: MiR-7-5p-mediated downregulation of PARP1 impacts DNA homologous recombination repair and resistance to doxorubicin in small cell lung cancer. BMC Cancer. 19:6022019. View Article : Google Scholar : PubMed/NCBI

17 

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

18 

Li L, Hao X, Qin J, Tang W, He F, Smith A, Zhang M, Simeone DM, Qiao XT, Chen ZN, et al: Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology. 146:1108–1118. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Zhou J, Zhang L, Zheng H, Ge W, Huang Y, Yan Y, Zhou X, Zhu W, Kong Y, Ding Y and Wang W: Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines. Cancer Med. 9:1115–1130. 2020. View Article : Google Scholar : PubMed/NCBI

20 

Cheng Q, Ouyang X, Zhang R, Zhu L and Song X: Senescence-associated genes and non-coding RNAs function in pancreatic cancer progression. RNA Biol. 17:1693–1706. 2020. View Article : Google Scholar : PubMed/NCBI

21 

Perez RF, Tejedor JR, Bayon GF, Fernández AF and Fraga MF: Distinct chromatin signatures of DNA hypomethylation in aging and cancer. Aging Cell. 17:e127442018. View Article : Google Scholar : PubMed/NCBI

22 

Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 15:2403–2413. 1997. View Article : Google Scholar : PubMed/NCBI

23 

Milanovic M, Fan DNY, Belenki D, Däbritz JHM, Zhao Z, Yu Y, Dörr JR, Dimitrova L, Lenze D, Monteiro Barbosa IA, et al: Senescence-associated reprogramming promotes cancer stemness. Nature. 553:96–100. 2018. View Article : Google Scholar : PubMed/NCBI

24 

Ye ZQ, Zou CL, Chen HB, Jiang MJ, Mei Z and Gu DN: MicroRNA-7 as a potential biomarker for prognosis in pancreatic cancer. Dis Markers. 2020:27821012020. View Article : Google Scholar : PubMed/NCBI

25 

Ohanna M, Giuliano S, Bonet C, Imbert V, Hofman V, Zangari J, Bille K, Robert C, Bressac-de Paillerets B, Hofman P, et al: Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). Genes Dev. 25:1245–1261. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Suresh B, Lee J, Kim KS and Ramakrishna S: The importance of ubiquitination and deubiquitination in cellular reprogramming. Stem Cells Int. 2016:67059272016. View Article : Google Scholar : PubMed/NCBI

27 

Dauer P, Nomura A, Saluja A and Banerjee S: Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters. Pancreatology. 17:7–12. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Binenbaum Y, Na'ara S and Gil Z: Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat. 23:55–68. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Guillon J, Petit C, Toutain B, Guette C, Lelièvre E and Coqueret O: Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity. Cell Cycle. 18:2385–2397. 2019. View Article : Google Scholar : PubMed/NCBI

30 

Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M and Alimonti A: Cellular senescence: Aging, cancer, and injury. Physiol Rev. 99:1047–1078. 2019. View Article : Google Scholar : PubMed/NCBI

31 

Demaria M, O'Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, et al: Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7:165–176. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Craske MG and Barlow DH: Nocturnal panic. J Nerv Ment Dis. 177:160–167. 1989. View Article : Google Scholar : PubMed/NCBI

33 

Hamed SS, Straubinger RM and Jusko WJ: Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells. Cancer Chemother Pharmacol. 72:553–563. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, et al: A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 15:978–990. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Ye Z, Chen H, Zhang T, Chen Z, Tian L and Gu D: MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells. Oncol Lett 21: 139, 2021.
APA
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., & Gu, D. (2021). MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells. Oncology Letters, 21, 139. https://doi.org/10.3892/ol.2020.12400
MLA
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., Gu, D."MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells". Oncology Letters 21.2 (2021): 139.
Chicago
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., Gu, D."MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells". Oncology Letters 21, no. 2 (2021): 139. https://doi.org/10.3892/ol.2020.12400
Copy and paste a formatted citation
x
Spandidos Publications style
Ye Z, Chen H, Zhang T, Chen Z, Tian L and Gu D: MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells. Oncol Lett 21: 139, 2021.
APA
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., & Gu, D. (2021). MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells. Oncology Letters, 21, 139. https://doi.org/10.3892/ol.2020.12400
MLA
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., Gu, D."MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells". Oncology Letters 21.2 (2021): 139.
Chicago
Ye, Z., Chen, H., Zhang, T., Chen, Z., Tian, L., Gu, D."MicroRNA‑7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF‑κB signaling in pancreatic cancer cells". Oncology Letters 21, no. 2 (2021): 139. https://doi.org/10.3892/ol.2020.12400
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