Functional characterization of melanoma-restricted genes (RMELs) associated with melanoma progression and BRAF V600E mutation

• Grant number: 12/24056-2
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): March 06, 2013
• Effective date (End): March 05, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Enilza Maria Espreafico
• Grantee: Cristiano Gonçalves Pereira
• Supervisor abroad: Michael A. Davies
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Local de pesquisa : University of Texas MD Anderson Cancer Center (MD Anderson), United States
• Associated to the scholarship: 10/16097-5 - Functional studies and prognostic value of a new gene associated with melanoma progression and oncogenic BRAF, BP.DR

Abstract

The gene HTARmel and RMELs (RMEL1, RMEL2 and RMEL3) genes were identified by an in silico study developed by our group, which aimed at identifying sequences derived exclusively of melanoma sources. We show previously that HTARmel is involved in melanoma progression and HTARmel and RMELs genes are associated with the oncogenic mutation of BRAF (V600E). The HTARmel knockdown by siRNA reduces the rates of cell proliferation in normal and anchorage-independent growth and reduces the clonogenic potential of melanoma cells. Results from pharmacological assays using BRAFV600E, MEK1/2 and PI3K specific inhibitors suggest that the HTARmel and RMELs genes are a transcriptional target of oncogenic BRAF and dependent on the PI3K pathway. One of the key objectives of the present work is to identify the molecular mechanisms that regulate the activation of these genes. The collaboration project with Dr. Michael Davies at MD Anderson Cancer Center will provide cutting edge tools that will enable us to describe the molecular pathways that influence the HTARmel and RMELs activation, investigate changes on key molecules of the MAPK and PI3K pathways regulated by genetic manipulation of HTARmel and RMELs (by knocking down approaches), analyze their roles in therapeutic resistance, and also combining expression data of HTARmel with RMELs from melanoma-specific RNAseq data bank, to investigate the role of these genes as novel prognostic markers or targets for melanoma treatment. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CARDOSO, CIBELE; SERAFIM, RODOLFO B.; KAWAKAMI, AKINORI; PEREIRA, CRISTIANO GONCALVES; ROSZIK, JASON; VALENTE, VALERIA; VAZQUEZ, VINICIUS L.; FISHER, DAVID E.; ESPREAFICO, ENILZA M. The lncRNA RMEL3 protects immortalized cells from serum withdrawal-induced growth arrest and promotes melanoma cell proliferation and tumor growth. PIGMENT CELL & MELANOMA RESEARCH, v. 32, n. 2, p. 303-314, MAR 2019. Web of Science Citations: 1.

GOEDERT, LUCAS; PEREIRA, CRISTIANO G.; ROSZIK, JASON; PLACA, JESSICA R.; CARDOSO, CIBELE; CHEN, GUO; DENG, WANLENG; YENNU-NANDA, VASHISHT GOPAL; SILVA, JR., WILSON A.; DAVIES, MICHAEL A.; ESPREAFICO, ENILZA M. RMEL3, a novel BRAF(V600E)-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma. ONCOTARGET, v. 7, n. 24, p. 36711-36718, JUN 14 2016. Web of Science Citations: 12.

CHEN, GUO; CHAKRAVARTI, NITIN; AARDALEN, KIMBERLY; LAZAR, ALEXANDER J.; TETZLAFF, MICHAEL T.; WUBBENHORST, BRADLEY; KIM, SANG-BAE; KOPETZ, SCOTT; LEDOUX, ALICIA A.; GOPAL, Y. N. VASHISHT; PEREIRA, CRISTIANO GONCALVES; DENG, WANLENG; LEE, JU-SEOG; NATHANSON, KATHERINE L.; ALDAPE, KENNETH D.; PRIETO, VICTOR G.; STUART, DARRIN; DAVIES, MICHAEL A. Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target. Clinical Cancer Research, v. 20, n. 21, p. 5537-5546, NOV 1 2014. Web of Science Citations: 62.