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ijms-26-08743-v2.pdf (11.29 MB)

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2025-09-08

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cc-by (c) Vinyals, Antònia et al., 2025
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/223486

Regulatory Mechanisms of SPARC Overexpression in Melanoma Progression

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https://doi.org/10.3390/ijms26178743

Abstract

The 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.

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Melanoma, Oncogens, Metàstasi

Subject (English)

Melanoma, Oncogenes, Metastasis

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

Citation

VINYALS, Antònia, et al. Regulatory Mechanisms of SPARC Overexpression in Melanoma Progression. International Journal of Molecular Sciences. 2025. Vol. 26, num. 17, pags. 8743. ISSN 1422-0067. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/223486

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