miR-665 expression predicts poor survival and promotes tumor metastasis by targeting NR4A3 in breast cancer

作者：Xinge Zhao, Jing-Ye Hu, Jun Tang, Yi Wei, Mei‐Yin Zhang, Rong Deng, Shi‐Juan Mai, Nuoqing Weng, Ruiqi Wang, Ji Liu, Huizhong Zhang, Jiehua He, Hui‐Yun Wang · 发表于：Cell Death and Disease · 年份：2019 · DOI：10.1038/s41419-019-1705-z · 被引用次数：127 · 研究领域：Nuclear Receptors and Signaling、Circular RNAs in diseases、MicroRNA in disease regulation

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstr...