Abstract：
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.
摘要：
配对相关同源异型盒1（PRRX1）是不同类型癌细胞中上皮-间质转化（EMT）的诱导剂。我们在痣中检测到低PRRX1表达，但在原发性人类黑色素瘤和携带BRAFV600E突变的细胞系中水平升高。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子.这里,我们表明，PRRX1的稳定消耗改善了黑色素瘤异种移植物的生长，并增加了远处自发性转移的数量，与对照组相比。我们提供的证据表明，PRRX1的丢失抵消了EMT表型，损害其他EMT相关转录因子的表达，引起ERK和信号转导和转录激活因子3（STAT3）信号通路的失调，并消除黑素瘤细胞的侵袭和迁移特性，同时触发增殖/黑素细胞基因的上调和神经一样标记神经生长因子受体（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。总的来说,我们的结果表明，PRRX1的丢失会触发侵入性程序的切换，和细胞向神经c干细胞（NCSC）样表型去分化，这说明了转移性侵袭性。
