Methylation of RECK and ALX3 genes in human melanoma

• Grant number: 11/19045-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2012
• Effective date (End): September 30, 2015
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Manoela Tiago dos Santos
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 12/05910-2 - Evaluation of RECK and ALX3 expression in cell lines and samples of melanoma patients resistant to vemurafenib (PLX4032) treatment, BE.EP.DR

Abstract

Human melanoma presents extreme chemoresistance and poor prognosis with a higher risk of lymphatic and hematogenous metastases, besides six to nine months of survival rate. There is no drug efficient in spite of recent advances in therapy as the verumafenib and ipilimumab, since the patients have still shown chemoresistance and tumor recurrence. The current treatment, therefore, is still based on the same used in the past decades even despite the improved therapeutic technology. Therefore, to know the biology of melanoma and to seek new targets are proeminent aims in this area. Tumor progression can be controlled by epigenetic events such as hypermethylation of tumor suppressor genes that are silenced during malignant transformation. The modulation of methylation is a promising therapeutic target because it can be reversed by treatment with demethylant agents, characterizing the epigenetic therapy. RECK gene is expressed in various normal human tissues, but it is suppressed during neoplastic transformation, and its silencing may be due to hypermethylation of its promoter. ALX3 gene presents its promoter hypermethylation in tumors of advanced stage neuroblastoma and colorectal tumors, however so far not been established the participation of these genes in transformation and evolution of melanoma. However, recently described that there are two transcripts from the chimeric fusion (exon 13/RECK gene and exon 3/ALX3 gene, and exon 14/RECK gene and exon 4/ALX3 gene). Although these transcripts do not generate functional chimeric protein, such a phenomenon, although rare, could illustrate a possible mechanism of suppression of RECK in melanoma and also elucidate the role of ALX3 in the progression of this tumor, which is the hypothesis of this work. Techniques of cellular and molecular biology, such as gene silencing and overexpression, Western blot,and quantitative PCR will be used to evaluate the expression and the methylation levels of RECK/ALX3, seeking to elucidate the role of such genes in melanoma.

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)

TIAGO, MANOELA; DE OLIVEIRA, EDSON MENDES; BROHEM, CARLA ABDO; PENNACCHI, PAULA COMUNE; PAES, RAFAEL DUARTE; HAGA, RAQUEL BRANDAO; CAMPA, ANA; DE MORAES BARROS, SILVIA BERLANGA; SMALLEY, KEIRAN S.; MARIA-ENGLER, SILVYA STUCHI. Fibroblasts Protect Melanoma Cells from the Cytotoxic Effects of Doxorubicin. TISSUE ENGINEERING PART A, v. 20, n. 17-18, p. 2412-2421, SEP 2014. (11/19045-9, 10/15919-1)

SANDRI, SILVANA; WATANABE, LUIS R. M.; DE OLIVEIRA, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; MIGLIORINI, SILENE; TIAGO, MANOELA; FELIPE-SILVA, ALOISIO; VAZQUEZ, VINICIUS DE LIMA; SOUZA, PAOLA DA COSTA; LOPES CONSOLARO, MARCIA EDILAINE; et al. Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance. PHARMACOLOGICAL RESEARCH, v. 159, SEP 2020. (17/04926-6, 17/26148-5, 12/05910-2, 11/19045-9, 16/16554-3, 13/05172-4, 15/10821-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SANTOS, Manoela Tiago dos. Mechanisms of epigenetic regulation and tumor clonal heterogeneity in human metastatic melanoma involving RECK gene. 2015. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.