配对相关同源盒 1 (PRRX1) 是不同类型癌细胞中上皮间质转化 (EMT) 的诱导剂。我们检测到痣中 PRRX1 表达较低，但在原发性人类黑色素瘤和携带 BRAFV600E 突变的细胞系中表达水平升高。 PRRX1 的高表达与属于 EMT 程序的基因的侵袭性和富集相关。相反，我们发现转移样本中 PRRX1 的缺失是黑色素瘤患者生存不良的独立预后预测因素。在这里，我们表明，与对照组相比，PRRX1 的稳定消耗可以改善黑色素瘤异种移植物的生长，并增加远处自发转移的数量。我们提供的证据表明，PRRX1 的缺失会抵消 EMT 表型，损害其他 EMT 相关转录因子的表达，导致 ERK 和信号转导子和转录激活子 3 (STAT3) 信号通路失调，并消除 EMT 的侵袭和迁移特性。黑色素瘤细胞，同时触发增殖/黑素细胞基因的上调以及神经嵴样标记物神经生长因子受体（NGFR；也称为神经营养蛋白受体 p75NTR）和神经细胞粘附分子 L1 (L1CAM) 的表达。总体而言，我们的结果表明，PRRX1 的缺失会触发侵袭性程序的转变，并且细胞去分化为神经嵴干细胞 (NCSC) 样表型，从而导致转移侵袭性。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Paired related homeobox 1 (PRRX1) is an inducer of epithelial-to-mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAFV600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT-related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up-regulation of proliferative/melanocytic genes and the expression of the neural-crest-like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de-differentiate towards a neural crest stem cell (NCSC)-like phenotype that accounts for the metastatic aggressiveness.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.