Open AccessMining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis
Author(s) -
Cláudia Souza,
Patrícia Xander,
Ana Carolina Monteiro,
Amanda Gonçalves dos Santos Silva,
Débora Castanheira Pereira da Silva,
Sabine Mai,
Viviane Bernardo,
José Daniel Lopes,
Miriam Galvonas Jasiulionis
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0044800
Subject(s) - melanoma , cancer research , epigenetics , biology , trichostatin a , metastasis , demethylating agent , melanocyte , cancer , histone deacetylase , gene expression profiling , dna methylation , gene expression , histone , gene , genetics
Background Metastatic melanoma is a highly aggressive skin cancer and currently resistant to systemic therapy. Melanomas may involve genetic, epigenetic and metabolic abnormalities. Evidence is emerging that epigenetic changes might play a significant role in tumor cell plasticity and metastatic phenotype of melanoma cells. Principal findings In this study, we developed a systematic approach to identify genes implicated in melanoma progression. To do this, we used the Affymetrix GeneChip Arrays to screen 34,000 mouse transcripts in melan-a melanocytes, 4C pre-malignant melanocytes, 4C11− non-metastatic and 4C11+ metastatic melanoma cell lines. The genome-wide association studies revealed pathways commonly over-represented in the transition from immortalized to pre-malignant stage, and under-represented in the transition from non-metastatic to metastatic stage. Additionally, the treatment of cells with 10 µM 5-aza-2′-deoxycytidine (5AzaCdR) for 48 hours allowed us to identify genes differentially re-expressed at specific stages of melan-a malignant transformation. Treatment of human primary melanocytes with the demethylating agent 5AzaCdR in combination to the histone deacetylase inhibitor Trichostatin A (TSA) revealed changes on melanocyte morphology and gene expression which could be an indicator of epigenetic flexibility in normal melanocytes. Moreover, changes on gene expression recognized by affecting the melanocyte biology ( NDRG2 and VDR ), phenotype of metastatic melanoma cells ( HSPB1 and SERPINE1 ) and response to cancer therapy ( CTCF , NSD1 and SRC ) were found when Mel-2 and/or Mel-3-derived patient metastases were exposed to 5AzaCdR plus TSA treatment. Hierarchical clustering and network analyses in a panel of five patient-derived metastatic melanoma cells showed gene interactions that have never been described in melanomas. Significance Despite the heterogeneity observed in melanomas, this study demonstrates the utility of our murine melanoma progression model to identify molecular markers commonly perturbed in metastasis. Additionally, the novel gene expression signature identified here may be useful in the future into a model more closely related to translational research.