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.
- skin neoplasms
- molecular biology
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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.
Patient consent for publication Not required.
Ethics approval Ethical approval (ACP0000174) was gained from the Nottingham Health Science Biobank Access Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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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