title: Ran signaling in melanoma: implications for the development of alternative therapeutic strategies.
abstract: We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.
authors.affiliation: Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Catania I-95124, Italy. Electronic address: emilia.caputo@igb.cnr.it.
authors.forename: Emilia
authors.initials: E
authors.lastname: Caputo
authors.affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine (DTM), Clinical Center (CC), Center for Human Immunology (CHI), National Institutes of Health (NIH), Bethesda, MD, United States; Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Valentino
authors.affiliation: Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy; Institute of Biosciences and BioResources-IBB, CNR, Naples I-8013, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Crispi
authors.affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine (DTM), Clinical Center (CC), Center for Human Immunology (CHI), National Institutes of Health (NIH), Bethesda, MD, United States.
authors.forename: Valeria
authors.initials: V
authors.lastname: De Giorgi
authors.affiliation: Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Fico
authors.affiliation: Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Catania I-95124, Italy.
authors.forename: Bartolomea
authors.initials: B
authors.lastname: Ficili
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Capone
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: AnnaMaria
authors.initials: A
authors.lastname: Anniciello
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Cavalcanti
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mozzillo
authors.affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine (DTM), Clinical Center (CC), Center for Human Immunology (CHI), National Institutes of Health (NIH), Bethesda, MD, United States; Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Catania I-95124, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Travali
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C120587:RAN protein, human; D020931:ran GTP-Binding Protein
keywords: Aurora kinase A in melanoma; Gene expression; Pathway analysis; Ran signaling; Targeted therapy