LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling
LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling
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LncRNA-NEF 通过顺式调节 FOXA2 和灭活 Wnt/β-catenin 信号传导拮抗上皮间质转化和癌症转移
DOI：
10.1038/s41388-017-0041-y
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Zhang, Jin-Fang
中科院分区：
文献类型：
--
作者：
Liang, Wei-Cheng;Ren, Jia-Lin;Zhang, Jin-Fang
新的证据表明长链非编码 RNA 广泛参与癌症进展。然而，这些lncRNA如何调节肿瘤发生的分子发病机制尚未完全阐明，尤其是在肝细胞癌（HCC）中。在这里，我们试图定义一种名为 lncRNA-NEF 的新型 lncRNA 在调节 HCC 上皮间质转化 (EMT) 中的作用。研究发现，lncRNA-NEF 被 EMT 抑制因子 FOXA2 转录激活，并且在 HCC 细胞系和临床样本中经常下调。虽然lncRNA-NEF表达的增强并不影响肿瘤细胞的生长，但lncRNA-NEF的异位表达显着抑制EMT程序和细胞迁移。动物研究证实，lncRNA-NEF 可减轻体内肿瘤转移并保护小鼠免受肿瘤引起的死亡。有趣的是，我们验证了lncRNA-NEF作为其邻近基因FOXA2的新型激活剂，形成正反馈环。随后的研究表明，lncRNA-NEF与β-catenin发生物理相互作用，增加GSK3β与β-catenin的结合，从而促进β-catenin的抑制性磷酸化，从而抑制Wnt/β-catenin信号传导并激活FOXA2表达。因此，我们的研究结果说明了一个包括 FOXA2 及其邻近基因 lncRNA-NEF 的新反馈环，这可能为 HCC 转移进展提供机制见解。
Emerging evidence indicates that the long noncoding RNAs extensively participate in cancer progression. Nevertheless, the molecular pathogenesis of how these lncRNAs regulate tumorigenesis has not been fully elucidated especially in hepatocellular carcinoma (HCC). Here, we sought to define the role of a novel lncRNA named lncRNA-NEF in modulating epithelial to mesenchymal transition (EMT) in HCC. It was found that the lncRNA-NEF was transcriptionally activated by EMT suppressor FOXA2 and frequently downregulated in HCC cell lines as well as clinical specimens. Although enhanced expression of lncRNA-NEF did not affect tumor cell growth, ectopic expression of lncRNA-NEF significantly suppressed EMT program and cell migration. Animal studies validated that lncRNA-NEF alleviated in vivo tumor metastasis and protected mice from tumor-induced mortality. Interestingly, we verified that lncRNA-NEF acted as a novel activator of its neighbor gene FOXA2, which formed a positive feedback loop. Subsequent studies revealed that lncRNA-NEF physically interacted with beta-catenin to increase the binding of GSK3 beta with beta-catenin and therefore promoted the inhibitory phosphorylation of beta-catenin, leading to the suppression on Wnt/beta-catenin signaling and activation of FOXA2 expression. Hence, our findings illustrated a novel feedback loop including FOXA2 and its neighboring gene lncRNA-NEF, which might provide mechanistic insights into the metastatic progress of HCC.