Vinyals, AntòniaFerreres Riera, Jose RamonCampos Martín, RafaelJorge Torres, Olga C.Mainez Villoro, JessicaPuig Butillé, Joan AntonMarcoval Caus, JoaquimPuig i Sardà, SusanaFabregat Romero, IsabelFabra Fres, Àngels2025-10-032025-10-032025-09-081422-0067https://hdl.handle.net/2445/223486The expression of the Secreted Protein, Acidic and Rich in Cysteine (SPARC) gene in human melanoma increases during progression and is associated with epithelial-to-mesenchymal transition (EMT), which is a major determinant of metastasis in melanoma patients. However, the underlying molecular mechanisms that control SPARC expression in this context remain elusive. Herein, we identified Paired-related homeobox 1 (PRRX1), an EMT transcription factor, as a transcriptional activator of SPARC by direct binding to the promoter, thereby increasing its activity. Moreover, we found a strong positive correlation between SPARC and PRRX1 expression levels in clinical samples and cell lines. Furthermore, the switch from the proliferative/melanocytic phenotype toward the invasive/mesenchymal-like phenotype favors the expression of TCF7L2, a beta-catenin cofactor, which, together with Sp1, binds to the proximal SPARC promoter, thereby bolstering protein expression. We also show that SPARC is a target of the miR-29 family, whose members are expressed in clinical melanoma samples and cell lines. Indeed, we found that miR-29b1 similar to a expression is inversely correlated with SPARC levels, and it is significantly reduced in samples with a mesenchymal-like phenotype. Taken together, SPARC expression in melanoma cells relies on transcriptional activation by PRRX1/TCF7L2-Sp1 and is modulated through miR-29b1 similar to a, which provides fine-tuning regulation over the switch between phenotypic states.31 p.application/pdfengcc-by (c) Vinyals, Antònia et al., 2025http://creativecommons.org/licenses/by/3.0/es/MelanomaOncogensMetàstasiMelanomaOncogenesMetastasisinfo:eu-repo/semantics/article2025-10-03info:eu-repo/semantics/openAccess40943659