Department of Thoracic/Head and Neck Medical Oncology and.
Department of Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Clin Invest. 2018 Apr 2;128(4):1267-1282. doi: 10.1172/JCI97225. Epub 2018 Feb 26.
Epithelial tumor cells undergo epithelial-to-mesenchymal transition (EMT) to gain metastatic activity. Competing endogenous RNAs (ceRNAs) have binding sites for a common set of microRNAs (miRs) and regulate each other's expression by sponging miRs. Here, we address whether ceRNAs govern metastasis driven by the EMT-activating transcription factor ZEB1. High miR-181b levels were correlated with an improved prognosis in human lung adenocarcinomas, and metastatic tumor cell lines derived from a murine lung adenocarcinoma model in which metastasis is ZEB1-driven were enriched in miR-181b targets. ZEB1 relieved a strong basal repression of α1 integrin (ITGA1) mRNA, which in turn upregulated adenylyl cyclase 9 mRNA (ADCY9) by sponging miR181b. Ectopic expression of the ITGA1 3'-untranslated region reversed miR-181b-mediated metastasis suppression and increased the levels of adenylyl cyclase 9 protein (AC9), which promoted tumor cell migration and metastasis. In human lung adenocarcinomas, ITGA1 and ADCY9 levels were positively correlated, and an AC9-activated transcriptomic signature had poor-prognostic value. Thus, ZEB1 initiates a miR-181b-regulated ceRNA network to drive metastasis.
上皮肿瘤细胞经历上皮-间充质转化（EMT）以获得转移活性。竞争内源性 RNA（ceRNA）具有一组共同的 microRNA（miR）结合位点，并通过海绵 miR 来调节彼此的表达。在这里，我们研究 ceRNA 是否控制 EMT 激活转录因子 ZEB1 驱动的转移。高 miR-181b 水平与人类肺腺癌的预后改善相关，并且从 ZEB1 驱动的小鼠肺腺癌模型中衍生的转移性肿瘤细胞系富含 miR-181b 靶标。ZEB1 解除了对 α1 整合素（ITGA1）mRNA 的强烈基础抑制，这反过来又通过海绵 miR181b 上调了腺苷酸环化酶 9 mRNA（ADCY9）。ITGA1 3'-非翻译区的异位表达逆转了 miR-181b 介导的转移抑制，并增加了腺苷酸环化酶 9 蛋白（AC9）的水平，从而促进了肿瘤细胞的迁移和转移。在人类肺腺癌中，ITGA1 和 ADCY9 水平呈正相关，并且 AC9 激活的转录组特征具有预后不良的价值。因此，ZEB1 启动了一个 miR-181b 调节的 ceRNA 网络来驱动转移。
