Identification of miRNA involved with melanoma genesis and epigenetic regulation of their expression

Abstract

miRNAs are small RNA molecules that bind to target mRNAs, promoting their destabilization. It is estimated that over 30% of all mRNAs are regulated by miRNAs. Thus, miRNAs are essential components in the control of several biological processes such as cell proliferation, apoptosis and survival. Cutaneous melanoma is the most deadly type of skin cancer and develops from the malignant transformation of melanocytes, a process that results from complex interactions between genetic factors (gene mutations and chromosomal abnormalities) and epigenetics. The most studied epigenetic mechanisms in humans are DNA methylation and post translational modifications in histones. Changes in epigenetic mechanisms can also alter the expression profile of miRNAs and contribute to tumor progression. Moreover, some studies suggest that miRNAs have key role in malignant transformation of cells. In our laboratory, it was developed a murine model of malignant transformation of melanocytes, in which different cell lines represent some phenotypes associated with melanoma. This model was established after submitting an immortalized, but non-tumorigenic, melanocyte lineage, melan-a, to cycles of anchorage blockade for 96 hours. During my graduate work differentially expressed miRNAs were identified along tumor progression, suggesting its importance in the development of melanoma. In this context, major objectives of this study are: 1) investigate the role of epigenetic mechanisms in modulating the expression of miRNAs and 2) evaluate the impact of aberrant expression of miRNAs in biological processes associated with the genesis and progression of melanoma. The expression of miRNAs will also be evaluated in human primary melanocytes and metastatic melanomas. (AU)