Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
Biomedicine Research Centre and Department of Surgery, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
J Pathol. 2016 Jun;239(2):186-96. doi: 10.1002/path.4716. Epub 2016 Apr 6.
The tricho-rhino-phalangeal syndrome 1 gene (TRPS1), which was initially found to be associated with tricho-rhino-phalangeal syndrome, is critical for the development and differentiation of bone, hair follicles and kidney. However, its role in cancer progression is largely unknown. In this study, we demonstrated that down-regulation of TRPS1 correlated with distant metastasis, tumour recurrence and poor survival rate in cancer patients. TRPS1 was frequently down-regulated in high-metastatic cancer cell lines from the breast, colon and nasopharynx. Silencing of TRPS1 stimulated epithelial-mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo, while TRPS1 over-expression exhibited the opposite effects. Using quantitative proteomics, FOXA1, a negative regulator of epithelial-mesenchymal transition (EMT), was shown to be down-regulated by TRPS1 knockdown. Ectopic expression of FOXA1 blocked the enhancement of EMT, migration and invasion induced by TRPS1 silencing. Mechanistically, TRPS1, acting as a transcription activator, directly induced FOXA1 transcription by binding to the FOXA1 promoter. We further showed that down-regulation of TRPS1 was induced by miR-373 binding to the 3' UTR of TRPS1. Over-expression of TRPS1, but not TRPS1 3' UTR, blocked the enhancement of migration and invasion induced by miR-373. Taken together, we consider that down-regulation of TRPS1 by miR-373, acting as a transcriptional activator, promotes EMT and metastasis by repressing FOXA1 transcription, expanding upon its previously reported role as a transcription repressor. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
三联征-指骨-外胚层发育不良 1 基因（TRPS1）最初被发现与三联征-指骨-外胚层发育不良有关，对骨骼、毛囊和肾脏的发育和分化至关重要。然而，其在癌症进展中的作用在很大程度上尚不清楚。在这项研究中，我们表明，TRPS1 的下调与癌症患者的远处转移、肿瘤复发和生存率降低有关。TRPS1 在来自乳腺、结肠和鼻咽的高转移性癌细胞系中经常下调。TRPS1 的沉默在体外刺激上皮-间充质转化（EMT）、迁移和侵袭，并在体内促进转移，而 TRPS1 的过表达则表现出相反的效果。使用定量蛋白质组学，FOXA1，上皮-间充质转化（EMT）的负调节剂，被证明是由 TRPS1 敲低下调的。FOXA1 的异位表达阻断了 TRPS1 沉默诱导的 EMT、迁移和侵袭的增强。在机制上，TRPS1 作为转录激活剂，通过结合 FOXA1 启动子直接诱导 FOXA1 转录。我们进一步表明，miR-373 结合到 TRPS1 的 3'UTR 诱导 TRPS1 的下调。TRPS1 的过表达，而不是 TRPS1 的 3'UTR，阻断了 miR-373 增强的迁移和侵袭。总之，我们认为 miR-373 通过结合 TRPS1 的 3'UTR 下调 TRPS1，通过抑制 FOXA1 转录，作为转录激活剂促进 EMT 和转移，扩大了其先前报道的作为转录抑制剂的作用。版权所有©2016 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd. 出版
