Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
J Cell Mol Med. 2020 May;24(9):5290-5303. doi: 10.1111/jcmm.15185. Epub 2020 Mar 30.
Patients with advanced breast cancer (BC) showed a higher incidence of regional and distant metastases. Sine oculis homeobox homolog 1 (SIX-1) has been confirmed to be a key tumorigenic and metastatic regulator in BC progression. Yet, molecular mechanisms behind SIX-1-induced BC metastases remain largely unknown. Here we found that SIX-1 was frequently up-regulated in BC and correlated with poor outcomes when tested in human BC tissue microarray. Then, we manipulated the expression of SIX-1 by via shRNA-mediated knockdown and lentivirus-mediated overexpression. Transwell assay in vitro and lung metastases model of nude mice in vivo showed that SIX-1 promoted BC cell invasion and migration in vitro, and facilitated metastases in vivo. Mechanistically, SIX-1 could promote the transcription of lncATB, which exerts critical pro-metastatic role in BC by directly binding to the miR-200 family, especially for miR-200c, to induce EMT and promote metastases. In conclusion, SIX-1 exerts its pro-metastatic role in BC through lncATB/miR-200s axis of EMT signalling pathway and could act as an important diagnostic marker as well as a significant therapeutic target for clinically advanced BC.
晚期乳腺癌 (BC) 患者表现出更高的区域性和远处转移发生率。 sine oculis homeobox homolog 1 (SIX-1) 已被证实是 BC 进展中关键的肿瘤发生和转移调节因子。然而，SIX-1 诱导的 BC 转移背后的分子机制在很大程度上仍不清楚。在这里，我们发现 SIX-1 在 BC 中经常上调，并在人 BC 组织微阵列中进行测试时与不良预后相关。然后，我们通过 shRNA 介导的敲低和慢病毒介导的过表达来操纵 SIX-1 的表达。体外 Transwell 测定和裸鼠体内肺转移模型表明，SIX-1 促进 BC 细胞体外侵袭和迁移，并促进体内转移。在机制上，SIX-1 可以促进 lncATB 的转录，lncATB 通过直接与 miR-200 家族，特别是 miR-200c 结合，发挥关键的促转移作用，从而诱导 EMT 并促进转移。总之，SIX-1 通过 EMT 信号通路的 lncATB/miR-200s 轴发挥其在 BC 中的促转移作用，可作为临床晚期 BC 的重要诊断标志物和治疗靶点。
