MicroRNAs regulate developmental events such as branching morphogenesis, epithelial to mesenchymal transition (EMT) and its reverse process mesenchymal to epithelial transition (MET). In this study, we performed small RNA sequencing of a breast epithelial progenitor cell line (D492), and its mesenchymal derivative (D492M) cultured in three-dimensional microenvironment. Among the most downregulated miRNAs in D492M was miR-203a, a miRNA that plays an important role in epithelial differentiation. Increased expression of miR-203a was seen in D492, concomitant with increased complexity of branching. When miR-203a was overexpressed in D492M, a partial reversion towards epithelial phenotype was seen. Gene expression analysis of D492M and D492MmiR-203a revealed peroxidasin, a collagen IV cross-linker, as the most significantly downregulated gene in D492MmiR-203a. Collectively, we demonstrate that miR-203a expression temporally correlates with branching morphogenesis and is suppressed in D492M. Overexpression of miR-203a in D492M induces a partial MET and reduces the expression of peroxidasin. Furthermore, we demonstrate that miR-203a is a novel repressor of peroxidasin. MiR-203-peroxidasin axis may be an important regulator in branching morphogenesis, EMT/MET and basement membrane remodeling.

中文翻译：

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MiR-203a 在乳腺祖细胞的分支形态发生和 EMT 过程中差异表达，并且是过氧化物酶的阻遏物

MicroRNA 调节发育事件，例如分支形态发生、上皮到间充质转化 (EMT) 及其逆向过程间充质到上皮转化 (MET)。在这项研究中，我们对在三维微环境中培养的乳腺上皮祖细胞系 (D492) 及其间充质衍生物 (D492M) 进行了小 RNA 测序。D492M 中下调幅度最大的 miRNA 是 miR-203a，这是一种在上皮分化中起重要作用的 miRNA。在 D492 中观察到 miR-203a 的表达增加，伴随着分支复杂性的增加。当 miR-203a 在 D492M 中过表达时，可以看到部分逆转为上皮表型。D492M 和 D492MmiR-203a 的基因表达分析揭示了过氧化物酶，一种胶原蛋白 IV 交联剂，作为 D492MmiR-203a 中最显着下调的基因。总的来说，我们证明 miR-203a 表达在时间上与分支形态发生相关并且在 D492M 中被抑制。D492M 中 miR-203a 的过表达诱导部分 MET 并降低过氧化物酶的表达。此外，我们证明 miR-203a 是过氧化物酶的新型阻遏物。MiR-203-过氧化物酶轴可能是分支形态发生、EMT/MET 和基底膜重塑的重要调节因子。