Mei Jie, Liu Yan, Yu Xinqian, Hao Leiyu, Ma Tao, Zhan Qiang, Zhang Yan, Zhu Yichao
Department of Oncology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
Wuxi College of Clinical Medicine, Nanjing Medical University, Wuxi, 214023, China.
Cell Death Discov. 2021 Aug 27;7(1):221. doi: 10.1038/s41420-021-00609-7.
Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a critical driver in facilitating metastasis in breast cancer (BrCa). However, molecular mechanisms for the regulation of DAAM1 activation are only partially elucidated. In this research, the expression levels of YWHAZ and DAAM1 were examined by immunohistochemistry (IHC) staining in BrCa tissues. The functional roles of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ)-DAAM1 axis and their regulator microRNA-613 (miR-613) in BrCa cells and associated molecular mechanisms were demonstrated in vitro. As results, the expression levels of DAAM1 and YWHAZ were significantly upregulated in BrCa tissues compared with normal tissues and remarkably associated with poor prognosis. Besides, DAAM1 and YWHAZ were positively correlated with each other in BrCa tissues. YWHAZ interacted and colocalized with DAAM1 in BrCa cells, which was essential for DAAM1-mediated microfilament remodeling and RhoA activation. Moreover, miR-613 directly targeted both YWHAZ and DAAM1, contributing to inhibiting BrCa cells migration via blocking the complex of YWHAZ-DAAM1. To sum up, these data reveal that YWHAZ regulates DAAM1 activation, and the YWHAZ-DAAM1 complex is directly targeted by the shared post-transcriptional regulator miR-613.
形态发生相关的无序蛋白激活因子1（DAAM1）是促进乳腺癌转移的关键驱动因素。然而，DAAM1激活的调控分子机制仅得到部分阐明。在本研究中，通过免疫组织化学（IHC）染色检测了乳腺癌组织中YWHAZ和DAAM1的表达水平。在体外证实了酪氨酸3-单加氧酶/色氨酸5-单加氧酶激活蛋白ζ（YWHAZ）-DAAM1轴及其调节因子微小RNA-613（miR-613）在乳腺癌细胞中的功能作用及相关分子机制。结果显示，与正常组织相比，乳腺癌组织中DAAM1和YWHAZ的表达水平显著上调，且与预后不良显著相关。此外，在乳腺癌组织中DAAM1和YWHAZ呈正相关。YWHAZ在乳腺癌细胞中与DAAM1相互作用并共定位，这对DAAM1介导的微丝重塑和RhoA激活至关重要。此外，miR-613直接靶向YWHAZ和DAAM1，通过阻断YWHAZ-DAAM1复合物来抑制乳腺癌细胞迁移。综上所述，这些数据表明YWHAZ调节DAAM1激活，且YWHAZ-DAAM1复合物是共同的转录后调节因子miR-613的直接作用靶点。
