State Key Laboratory of Oncology in Southern China, Guangzhou, China.
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer Res. 2018 Mar 1;78(5):1241-1252. doi: 10.1158/0008-5472.CAN-17-1545. Epub 2018 Jan 8.
Epithelial-to-mesenchymal transition (EMT) promotes metastasis, which is the main cause of bladder urothelial carcinoma-related death. Loss of the candidate tumor-suppressor gene Nkx2.8 has been associated with urothelial carcinoma lymph node metastasis. Here, we show that enforced expression of Nkx2.8 is sufficient to inhibit EMT, reduce motility, and blunt invasiveness of urothelial carcinoma cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of the EMT inducer Twist1 in urothelial carcinoma cells, at both the level of mRNA and protein accumulation. Nkx2.8 bound directly to the promoter region of this gene and transcriptionally repressed its expression. Twist1 upregulation reversed EMT inhibition by Nkx2.8, restoring the invasive phenotype of urothelial carcinoma cells. In clinical urothelial carcinoma specimens, expression of Nkx2.8 inversely correlated with Twist1 expression, and urothelial carcinoma patients with Nkx2.8 positivity and low Twist1 expression displayed the best prognosis. Our findings highlight the Nkx2.8-Twist1 axis as candidate target for therapeutic intervention in advanced urothelial carcinoma. These findings highlight a novel EMT signaling axis as a candidate target for therapeutic intervention in advanced urothelial carcinomas. .
上皮-间充质转化（EMT）促进转移，这是膀胱癌相关死亡的主要原因。候选肿瘤抑制基因 Nkx2.8 的丢失与膀胱癌淋巴结转移有关。在这里，我们表明，强制表达 Nkx2.8 足以抑制 EMT、降低运动性并削弱膀胱癌细胞的侵袭性。机制研究表明，Nkx2.8 负调控 EMT 诱导因子 Twist1 在膀胱癌细胞中的表达，无论是在 mRNA 水平还是蛋白积累水平。Nkx2.8 直接结合到该基因的启动子区域，并转录抑制其表达。Twist1 的上调逆转了 Nkx2.8 对 EMT 的抑制作用，恢复了膀胱癌细胞的侵袭表型。在临床膀胱癌标本中，Nkx2.8 的表达与 Twist1 的表达呈负相关，并且 Nkx2.8 阳性和 Twist1 低表达的膀胱癌患者预后最佳。我们的研究结果强调了 Nkx2.8-Twist1 轴作为晚期膀胱癌治疗干预的候选靶点。这些发现强调了一种新的 EMT 信号轴作为晚期膀胱癌治疗干预的候选靶点。
