Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 200031, Shanghai, China.
University of Chinese Academy of Sciences, 200031, Shanghai, China.
Nat Commun. 2019 Apr 9;10(1):1637. doi: 10.1038/s41467-019-09649-1.
The competitive endogenous RNA (ceRNA) hypothesis suggests an intrinsic mechanism to regulate biological processes. However, whether the dynamic changes of ceRNAs can modulate miRNA activities remains controversial. Here, we examine the dynamics of ceRNAs during TGF-β-induced epithelial-to-mesenchymal transition (EMT). We observe that TGFBI, a transcript highly induced during EMT in A549 cells, acts as the ceRNA for miR-21 to modulate EMT. We further identify FN1 as the ceRNA for miR-200c in the canonical SNAIL-ZEB-miR200 circuit in MCF10A cells. Experimental assays and computational simulations demonstrate that the dynamically induced ceRNAs are directly coupled with the canonical double negative feedback loops and are critical to the induction of EMT. These results help to establish the relevance of ceRNA in cancer EMT and suggest that ceRNA is an intrinsic component of the EMT regulatory circuit and may represent a potential target to disrupt EMT during tumorigenesis.
竞争性内源 RNA（ceRNA）假说提示了一种内在的机制来调节生物过程。然而，ceRNAs 的动态变化是否能调节 miRNA 的活性仍存在争议。在这里，我们研究了 TGF-β诱导的上皮间质转化（EMT）过程中 ceRNAs 的动态变化。我们观察到，TGFBI 在 A549 细胞 EMT 过程中高度诱导，作为 miR-21 的 ceRNA 来调节 EMT。我们进一步鉴定出 FN1 是 MCF10A 细胞中经典 SNAIL-ZEB-miR200 回路中 miR-200c 的 ceRNA。实验和计算模拟表明，动态诱导的 ceRNAs 与经典的双负反馈环直接耦合，对于 EMT 的诱导至关重要。这些结果有助于确立 ceRNA 在癌症 EMT 中的相关性，并表明 ceRNA 是 EMT 调控回路的内在组成部分，可能代表了在肿瘤发生过程中破坏 EMT 的潜在靶点。
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