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

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.

• 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, Mohamed El-Tanani, Mohammad Ilyas
• Journal: Journal of clinical pathology (J Clin Pathol) Vol. 75 Issue 1 Pg. 24-29 (Jan 2022) ISSN: 1472-4146 [Electronic] England
• PMID: 33234696 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• RAN protein, human
• Proto-Oncogene Proteins c-met
• ran GTP-Binding Protein

Topics

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Melanoma (diagnosis, pathology)
• Neoplasm Invasiveness
• Prognosis
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Signal Transduction
• Skin Neoplasms (diagnosis, pathology)
• ran GTP-Binding Protein (genetics, metabolism)