Original Articles: Basic scienceThe 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 vitroJacomasso, Thiagoa; Ribas, Hennrique Tabordaa; Trombetta-Lima, Marinab,,c; Silberspitz Konig, Michellec; Trindade, Edvaldo da Silvad; Martinez, Glaucia Reginaa; Sogayar, Mari Cleideb,,c; Winnischofer, Sheila Maria Brochadoa,,d,,eAuthor Information aPostgraduate Program in Biochemistry Sciences, Sector of Biological Sciences, Federal University of Paraná, Curitiba bCell and Molecular Therapy Center (NUCEL), Medical School cDepartment of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo dDepartment of Cell Biology, Federal University of Paraná eDepartment of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil Received 2 March 2019 Accepted 25 September 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.melanomaresearch.com. Correspondence to Sheila Maria Brochado Winnischofer, PhD, Universidade Federal do Parana Setor de Ciencias Biologicas, Rua Cel. Francisco H. dos Santos 210, Jardim das Américas – Curitiba, PR. CEP: 81531-980, Brazil, Tel: +55 41 336 11673; fax: +55 41 3266 2042; e-mail: email@example.com Melanoma Research: June 2020 - Volume 30 - Issue 3 - p 223-234 doi: 10.1097/CMR.0000000000000650 Buy SDC Metrics Abstract 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.