Novel Candidate Biomarkers in Melanomas Figure 2. Pre-Malignant Melanocytes and Metastatic Melanomas Shared Deregulated Pathways. (A) Gene expression profiles of melan- a, 4C, 4C11– and 4C11+ cell lines revealed differentially up- and down-regulated genes in the transitions associated with malignant transformation of melan-a melanocytes (from melan-a to 4C, 4C to 4C112, and 4C112 to 4C11+ cells). Transcripts were selected as statistically significant by the unpairwise two-class SAM analysis (FDR and Q-values,0.05). (B) PANTHER software was used to determine pathway profiles deregulated in the course of melanoma progression. (C) Venn diagram pointed out pathways deregulated at specific stages of melan-a malignant transformation. (D) Identification of pathways commonly over-represented in 4C pre-malignant melanocytes in relation to melan-a cells, and under-represented in 4C11+ metastatic melanoma cell line in relation to 4C112 non-metastatic melanoma cells. (E) Epigenetic signature as a candidate marker associated with the transition from non-metastatic to metastatic phenotype. ma: immortalized, but non-tumorigenic, melan-a melanocyte lineage; 4C: pre-malignant melanocyte lineage; 4C112: non-metastatic melanoma cell line, and 4C11+: metastatic melanoma cell line. doi:10.1371/journal.pone.0044800.g002 4C112 non-metastatic melanoma cell line in comparison to 4C pre-malignant melanocyte lineage, and our list of over-expressed genes upon 5AzaCdR treatment in 4C112 melanoma cell; III) intersection between genes found significantly down-regulation in 4C11+ metastatic melanoma cell line in comparison to 4C112 non-metastatic melanoma cell, and our list of over-expressed genes PLOS ONE | www.plosone.org 5 September 2012 | Volume 7 | Issue 9 | e44800