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Open AccessArticle

RKIP Regulates Differentiation-Related Features in Melanocytic Cells

Department of Cell Biology and Histology, Faculty of Medicine and Nursing, UPV/EHU, 48940 Leioa, Spain
Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
Department of Physiology, Faculty of Medicine and Nursing, UPV/EHU, 48940 Leioa, Spain
Department of Psychology, Carnegie Mellon University, Pittsburg, PA 15213, USA
Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, UPV/EHU, 48940 Leioa, Spain
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1451;
Received: 11 May 2020 / Revised: 29 May 2020 / Accepted: 30 May 2020 / Published: 3 June 2020
(This article belongs to the Special Issue Targeted Therapies for Melanoma)
Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of key signaling pathways involved in the aggressive tumor phenotype and shows decreased expression in several types of cancers. However, little is known about RKIP in melanoma or regarding its function in normal cells. We examined the role of RKIP in both primary melanocytes and malignant melanoma cells and evaluated its diagnostic and prognostic value. IHC analysis revealed a significantly higher expression of RKIP in nevi compared with early-stage (stage I–II, AJCC 8th) melanoma biopsies. Proliferation, wound healing, and collagen-coated transwell assays uncovered the implication of RKIP on the motility but not on the proliferative capacity of melanoma cells as RKIP protein levels were inversely correlated with the migration capacity of both primary and metastatic melanoma cells but did not alter other parameters. As shown by RNA sequencing, endogenous RKIP knockdown in primary melanocytes triggered the deregulation of cellular differentiation-related processes, including genes (i.e., ZEB1, THY-1) closely related to the EMT. Interestingly, NANOG was identified as a putative transcriptional regulator of many of the deregulated genes, and RKIP was able to decrease the activation of the NANOG promoter. As a whole, our data support the utility of RKIP as a diagnostic marker for early-stage melanomas. In addition, these findings indicate its participation in the maintenance of a differentiated state of melanocytic cells by modulating genes intimately linked to the cellular motility and explain the progressive decrease of RKIP often described in tumors. View Full-Text
Keywords: RKIP; melanocytes; melanoma; transcriptome analysis; cell motility; differentiation; biomarker RKIP; melanocytes; melanoma; transcriptome analysis; cell motility; differentiation; biomarker
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Penas, C.; Apraiz, A.; Muñoa, I.; Arroyo-Berdugo, Y.; Rasero, J.; Ezkurra, P.A.; Velasco, V.; Subiran, N.; Bosserhoff, A.K.; Alonso, S.; Asumendi, A.; Boyano, M.D. RKIP Regulates Differentiation-Related Features in Melanocytic Cells. Cancers 2020, 12, 1451.

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