Vinyals Antònia, Ferreres Josep R, Campos-Martín Rafael, Torres Olga J C, Mainez Jessica, Puig-Butillé Joan A, Marcoval Joaquim, Puig Susana, Fabregat Isabel, Fabra Àngels
TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII-Instituto de Salud Carlos III, 28029 Madrid, Spain.
Int J Mol Sci. 2025 Sep 8;26(17):8743. doi: 10.3390/ijms26178743.
The expression of the Secreted Protein, Acidic and Rich in Cysteine () 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 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 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 β-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-29b1a 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-29b1a, which provides fine-tuning regulation over the switch between phenotypic states.
分泌性蛋白质，富含酸性半胱氨酸（SPARC）基因在人类黑色素瘤进展过程中的表达增加，且与上皮-间质转化（EMT）相关，而EMT是黑色素瘤患者转移的主要决定因素。然而，在此背景下控制SPARC表达的潜在分子机制仍不清楚。在本文中，我们鉴定出配对相关同源盒1（PRRX1），一种EMT转录因子，通过直接结合启动子作为SPARC的转录激活因子，从而增加其活性。此外，我们在临床样本和细胞系中发现SPARC与PRRX1表达水平之间存在强正相关。此外，从增殖/黑素细胞表型向侵袭/间充质样表型的转变有利于β-连环蛋白辅因子TCF7L2的表达，TCF7L2与Sp1一起结合到近端SPARC启动子上，从而增强蛋白质表达。我们还表明，SPARC是miR-29家族的一个靶点，其成员在临床黑色素瘤样本和细胞系中表达。事实上，我们发现miR-29b1a的表达与SPARC水平呈负相关，并且在具有间充质样表型的样本中显著降低。综上所述，黑色素瘤细胞中SPARC的表达依赖于PRRX1/TCF7L2-Sp1的转录激活，并通过miR-29b1a进行调节，这为表型状态之间的转换提供了微调调控。
