Mining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis

Autor(es)

de Souza, Camila Ferreira ^[1] ; Xander, Patricia ^[2] ; Monteiro, Ana Carolina ^[1] ; dos Santos Silva, Amanda Goncalves ^[3] ; Pereira da Silva, Debora Castanheira ^[4] ; Mai, Sabine ^[5] ; Bernardo, Viviane ^[6] ; Lopes, Jose Daniel ^[7] ; Jasiulionis, Miriam Galvonas ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo - Brazil

^[3] Hosp AC Camargo Fund Antonio Prudente, CIPE, Sao Paulo - Brazil

^[4] Hosp AC Camargo Fund Antonio Prudente, Dept Oncol Cutanea, Sao Paulo - Brazil

^[5] Univ Manitoba, Manitoba Inst Cell Biol, Canc Care Manitoba, Winnipeg, MB - Canada

^[6] Univ Fed Sao Paulo, Dept Informat Saude, Sao Paulo - Brazil

^[7] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 7, n. 9 SEP 11 2012.
• Citações Web of Science: 10

Resumo

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 mM 5-aza-29-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. (AU)

• Processo FAPESP: 11/12306-1 - Mecanismos epigenéticos como mediadores da transformação maligna de melanócitos associada a condições sustentadas de estresse
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/51462-9 - Assinaturas moleculares da progressao do melanoma.
• Beneficiário: Camila Ferreira de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 06/61293-1 - Contribuição da metilação de DNA na carcinogênese
• Beneficiário: Miriam Galvonas Jasiulionis
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores