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Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion

Elsheikh, Somaia; Kouzoukakis, Ilias; Fielden, Catherine; Li, Wei; Lashin, Shaimaa Elsaid; Khair, Nadia; Raposo, Teresa Pereira; Fadhil, Wakkas; Rudland, Philip; Aleskandarany, Mohammed; Patel, Poulam; El-Tanani, Mohamed; Ilyas, Mohammad

Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion Thumbnail


Authors

Somaia Elsheikh

Ilias Kouzoukakis

Catherine Fielden

Wei Li

Shaimaa Elsaid Lashin

Nadia Khair

Teresa Pereira Raposo

Wakkas Fadhil

Philip Rudland

Mohammed Aleskandarany

POULAM PATEL POULAM.PATEL@NOTTINGHAM.AC.UK
Professor of Clinical Oncology

Mohamed El-Tanani



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 [less than] 0.001) and cell invasion (p [less than] 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.

Citation

Elsheikh, S., Kouzoukakis, I., Fielden, C., Li, W., Lashin, S. E., Khair, N., Raposo, T. P., Fadhil, W., Rudland, P., Aleskandarany, M., Patel, P., El-Tanani, M., & Ilyas, M. (2022). Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion. Journal of Clinical Pathology, 75(1), 24-29. https://doi.org/10.1136/jclinpath-2020-206871

Journal Article Type Article
Acceptance Date Oct 6, 2020
Online Publication Date Nov 24, 2020
Publication Date 2022-01
Deposit Date Dec 30, 2020
Publicly Available Date Jan 6, 2021
Journal Journal of Clinical Pathology
Print ISSN 0021-9746
Electronic ISSN 1472-4146
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 75
Issue 1
Pages 24-29
DOI https://doi.org/10.1136/jclinpath-2020-206871
Keywords Pathology and Forensic Medicine; General Medicine
Public URL https://nottingham-repository.worktribe.com/output/5183932
Publisher URL https://jcp.bmj.com/content/early/2020/11/24/jclinpath-2020-206871

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