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The role of EIF5A2 and eIF4E translation factors in human cutaneous melanoma Khosravi, Shahram

Abstract

Cutaneous melanoma is a life-threatening skin cancer due to its poorly understood invasiv nature and high metastatic potential. On the other hand, translational dysregulation has been shown to have an important role in the development and progression of cancer. In this study we investigated the role of two translational factors called eukaryotic translation initiation factor 5A2 (EIF5A2) and eukaryotic translation initiation factor 4E (eIF4E) in melanoma. Using tissue microarray (TMA) we showed that eIF4E expression and nuclear and cytoplasmic EIF5A2 expression increased from dysplastic nevi to primary melanomas, and further increased in metastatic melanomas. The expression of eIF4E and both EIF5A2 forms were correlated with melanoma thickness and AJCC stages and were inversely correlated with the 5-year survival of melanoma patients. TMA data also revealed that nuclear EIF5A2, cytoplasmic EIF5A2 and eIF4E expression were all directly correlated with MMP-2 expression which is an important factor for promoting cancer cell invasion. In addition, in vitro analysis revealed that both melanoma cell invasion and MMP-2 activity decreased as a result of EIF5A2 or eIF4E knockdown indicating that EIF5A2 and eIF4E may be responsible for increasing melanoma cell invasiveness at least partly through increasing MMP-2 activity. Our experiments also showed that EIF5A2 is a novel downstream target of p-Akt. Additionally, we indicated that both EIF5A2 and eIF4E may play a role in EMT by upregulating mesenchymal markers and downregulating epithelial markers. eIF4E knockdown also decreased cell proliferation and increased apoptosis and caused a decrease in c-myc and BCL-2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Nuclear and cytoplasmic EIF5A2 expression were found to be significantly correlated, and simultaneous expression of both was significantly associated with poor overall and disease-specific 5-year survival of melanoma patients. This correlation; however, was not perfect which may indicate the differential regulation of nuclear and cytoplasmic EIF5A2 expression in melanoma. Multivariate Cox regression analysis revealed that eIF4E expression, nuclear and cytoplasmic EIF5A2 expression and the combination of the last two were an adverse independent prognostic factor for melanoma patients. Therefore, they have the potential to be used as prognostic therapeutic markers in melanoma.

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