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Functional characterization of the BRAFV600E-correlated long noncoding RNA RMEL3 in melanoma

Grant number: 17/16363-6
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): November 01, 2017
Effective date (End): October 31, 2018
Field of knowledge:Biological Sciences - Biology
Principal Investigator:Enilza Maria Espreafico
Grantee:Lucas Goedert
Supervisor abroad: Eleonora Leucci
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University of Leuven (KU Leuven), Belgium  
Associated to the scholarship:14/07726-0 - Genomic and functional characterization of genes with expression restricted to melanoma (RMELs), BP.DD

Abstract

Melanoma is the most aggressive form of skin cancer. Targeted therapies against BRAFV600 mutations, which are present in ~60% of melanomas, achieve impressive initial clinical responses, but the development of acquired resistance to these agents is almost universal. The identification of additional melanoma oncogenic mechanisms initiated by oncogenic BRAF will facilitate the development of more long-term effective therapeutic approaches. In this context, we have identified a long noncoding RNA called RMEL3 that has enriched expression in melanoma and correlates with BRAFV600E. Through functional experiments and bioinformatic analyses we have demonstrated that RMEL3 is involved in the modulation of the MAPK and PI3K pathways. Silencing RMEL3 results in the upregulation of the major melanoma tumor suppressor PTEN and the senescence regulators p21 and p27, while reduces the protein concentration of BRAF, pAKT and pRB. This modulation upon RMEL3 knockdown drastically reduces the clonogenic capability of BRAFV600E melanoma cells and increases the accumulation of cells in G1 phase and sub G0/G1. However, its remains to be elucidated RMEL3 molecular mechanism, which will allow a better understanding of its oncogenic activity and clinical relevance. In this BEPE proposal we intend to use advanced molecular and cellular techniques, such as lncRNA endogenous pulldown, mass spectrometry and in vivo experiments, to accurately determine RMEL3 function in melanoma cells, which will be supported by the extensive and specialized experience in lncRNAs of Prof. Eleonora Leucci.