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Original research
Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion
  1. Somaia Elsheikh1,2,3,
  2. Ilias Kouzoukakis1,
  3. Catherine Fielden1,
  4. Wei Li1,
  5. Shaimaa Elsaid Lashin1,4,
  6. Nadia Khair5,
  7. Teresa Pereira Raposo1,
  8. Wakkas Fadhil1,
  9. Philip Rudland6,
  10. Mohammed Aleskandarany1,
  11. Poulam Patel1,
  12. Mohamed El-Tanani7,
  13. Mohammad Ilyas1
  1. 1 Division of Cancer and Stem Cell, University of Nottingham, Nottingham, UK
  2. 2 Cellular Pathology Department, Nottingham University Hospitals NHS Trust, Nottingham, Nottingham, UK
  3. 3 Pathology Department, Menoufia University Faculty of Medicine, Shebin El-Kom, Egypt
  4. 4 Dermatology, Menoufia University Faculty of Medicine, Shebin El-Kom, Egypt
  5. 5 Histology, Menoufia University Faculty of Medicine, Shebin El-Kom, Egypt
  6. 6 School of Biological Sciences, University of Liverpool, Liverpool, UK
  7. 7 School of Chemistry and Biosciences, University of Bradford, Bradford, West Yorkshire, UK
  1. Correspondence to Dr Somaia Elsheikh, Division of Cancer and Stem Cell, University of Nottingham, Nottingham, UK; Somaia.elsheikh{at}nottingham.ac.uk

Abstract

Aims Ran GTPase is involved in nucleocytoplasmic shuttling of proteins and is overexpressed in several cancers. The expression of Ran in malignant melanoma (MM) and its functional activity have not been described and were investigated in this study.

Methods The prognostic value of Ran expression was tested in a series of 185 primary cutaneous MM cases using immunohistochemistry. The functional activity of Ran was investigated in the two melanoma cell lines. Ran expression was knocked down using two siRNAs and the effect on the expression of the c-Met oncogene, a potential downstream target of Ran, was tested. Functional effects of Ran knockdown on cell motility and cell proliferation were also assessed.

Results Positive Ran expression was seen in 12.4% of MM and was associated with advanced clinical stage and greater Breslow thickness. Positive expression was an independent marker of shorter overall survival (p=0.023). Knockdown of Ran results in decreased expression of c-Met and the downstream c-met signalling targets ERK1/2. There was a significant reduction in cell migration (p<0.001) and cell invasion (p<0.001). c-Met knockdown decreased the expression of Ran through MAPK and PI3K-AKT in A375 cell line, inhibited the cell viability and migration of both A375 and G361 melanoma cell lines while invasion was enhanced.

Conclusion Ran is a poor prognostic marker in cutaneous MM. It upregulates expression of the oncogene c-Met and, possibly through this, it promotes cell motility which may in turn promote metastasis.

  • melanoma
  • skin neoplasms
  • oncogenes
  • molecular biology

Data availability statement

All data generated or analysed during this study are included in this published article and its supplemental file.

https://doi.org/10.1136/jclinpath-2020-206871

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    Data availability statement

    All data generated or analysed during this study are included in this published article and its supplemental file.

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    Footnotes

    • SE and IK are joint first authors.

    • Handling editor Dhirendra Govender.

    • SE, ME-T and MI contributed equally.

    • Contributors SE, ME-T, PR, PP, MI: Study design manuscript writing. IK, CF, WL, SEL, NK,TPR, WF, MA: Practical experiments, data collection, data analysis. manuscript writing.

    • Funding This work was partially supported by the University of Nottingham and the Supreme Council of Universities, Egypt.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.