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Research in the early stages of melanoma genesis of key regulators of epithelial-mesenchymal transition and stem cell-like phenotype epigenetically controlled

Grant number: 11/18959-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2012
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Miriam Galvonas Jasiulionis
Grantee:Alice Santana Morais
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):14/01168-5 - Identification of important targets associated with stem-like state and epithelial mesenchymal transition along melanocyte malignant transformation, BE.EP.DR

Abstract

Although less prevalent among skin cancers, cutaneous melanoma represents the most dangerous form and is responsible for most deaths associated with skin cancer. Primary cutaneous melanoma is often curable when early diagnosed. However, its extreme clinical metastatic melanoma detains the worst prognosis and remains one of the most resistant tumor types. It is known that the loss of the delicate homeostatic balance established between keratinocytes and melanocytes lays an effective role in melanoma genesis. Several hypotheses are investigated to explain the development of this neoplasm, involving specific genetic events, as well as the influence of environmental factors. It is believed that epigenetic events, under the microenvironment influence, are also acting in melanocyte malignant transformation. The epigenetic regulation is one of the major interests to the scientific field because of its importance in development, physiologically regulating key events of cell biology. Moreover, the dynamism and reversibility of epigenetic changes make them viable targets for therapeutic interventions. Therefore, efforts have been made in order to identify DNA methylation profile in different types of cancer, making it a molecular marker that may aid in the diagnosis and accurate prognostic of these diseases. In this context, the objective is to evaluate the role of genes Chd1 (chromatin remodeling) and Snai1 (transcriptional repressor), identified as differentially expressed during the malignant transformation of melanocytes. Previous data obtained by Methylight technique and expression assays with lineages treated with epigenetic drugs suggest a strong influence of epigenetic mechanisms in control of expression of these genes. This study involves a pre-established murine model in which it was observed that the acquisition of metastatic phenotype occurred after intense chromatin reorganization marked by transient changes in the early stages of malignant transformation, as acquisition of features of pluripotency and epithelial-mesenchymal transition-like activation. Among the various genes to be responsible for cellular adaptation to the new environment, and Chd1 Snai1 are mainly associated to intermediate stage of the murine model. A more precise research on the importance of these genes throughout the evolution process of malignant transformation, as well as potential mechanisms and pathways leading to activation of the same, will certainly bring relevant information about the development and progression of malignant melanoma, as well as the possible contribution of epigenetic events in regulating these processes. In addition to scientific advances, this study may provide great tools and approaches to early diagnosis and effective treatment of this malignancy.