The alternatively spliced RECK transcript variant 3 is a predictor of poor survival for melanoma patients being upregulated in aggressive cell lines and modulating MMP gene expression in vitro

Autor(es)

Jacomasso, Thiago ^[1] ; Ribas, Hennrique Taborda ^[1] ; Trombetta-Lima, Marina ^{[2, 3]} ; Konig, Michelle Silberspitz ^[2] ; Trindade, Edvaldo Silva ^[4] ; Martinez, Glaucia Regina ^[1] ; Sogayar, Mari Cleide ^{[2, 3]} ; Winnischofer, Sheila Maria Brochado ^{[4, 1, 5]}

Afiliação do(s) autor(es)

^[1] Univ Fed Parana, Sect Biol Sci, Postgrad Program Biochem Sci, Curitiba, Parana - Brazil

^[2] Univ Sao Paulo, Chem Inst, Dept Biochem, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Med Sch, Cell & Mol Therapy Ctr NUCEL, Sao Paulo - Brazil

^[4] Univ Fed Parana, Dept Cell Biol, Curitiba, Parana - Brazil

^[5] Univ Fed Parana, Dept Biochem & Mol Biol, Curitiba, Parana - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Melanoma Research; v. 30, n. 3, p. 223-234, JUN 2020.
• Citações Web of Science: 0

Resumo

The reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene was described as a tumor suppressor gene two decades ago. Recently, novel alternatively spliced products of this gene have been identified. Of these, the transcript variant 3 (RECKVar3) was shown to display tumor-facilitating effects in astrocytoma cells in vitro, with a higher RECKVar3/canonical RECK expression ratio being correlated with lower survival rates of patients. However, the regulatory mechanisms through which the cell controls the production and maintenance of these alternative transcripts, as well as their expression in other tumor types, remain elusive. Thus, the aim of this study is to investigate the role of the alternatively spliced transcripts from the RECK gene in melanoma progression as well as their regulation mechanism. To this end, we analyzed data from the Cancer Genome Atlas network and experimental data obtained from a panel of cell lines to show that high levels of RECKVar3 are predictive of poor survival. We also show that the MAPK and PI3K signaling pathways clearly play a role in determining the alternative-to-canonical ratio in vitro. Finally, we show that overexpression of the RECKVar3 protein upregulates matrix metalloproteinases (MMP)-9 and MMP-14 mRNA, while downregulating their inhibitor, tissue inhibitor of metalloproteinase (TIMP)3, and that RECKVar3-specific knockdown in the 1205Lu melanoma cell line hampered upregulation of the MMP9 mRNA promoted by the MEK1/2 inhibitor U0126. Taken together, our data complement the evidence that the RECK gene has a dual role in cancer, contributing to better understanding of the signaling cues, which dictate the melanoma invasive potential. (AU)

• Processo FAPESP: 16/18277-7 - Análise do papel do gene supressor de tumor Reck em divisões celulares assimétricas
• Beneficiário: Marina Trombetta Lima
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 08/53971-5 - Análise do papel do gene supressor de tumor RECK na regulação do ciclo celular e caracterização de sua isoforma alternativa
• Beneficiário: Marina Trombetta Lima
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 16/05311-2 - Medicina regenerativa visando à terapia de doenças crônico-degenerativas (câncer e diabetes)
• Beneficiário: Mari Cleide Sogayar
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/26328-8 - Análise comparativa do papel do gene supressor de tumor RECK na sub-população de células-tronco tumorais de GBM e em precursores neurais normais.
• Beneficiário: Marina Trombetta Lima
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado