Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis.
Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis.
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TGF-β/SMAD/lnc-UTTGF 正反馈环的鉴定及其在肝癌转移中的作用。
DOI：
10.1038/s41392-021-00781-3
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发表时间：
2021-11-17
影响因子：
39.3
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Wu MZ;Yuan YC;Huang BY;Chen JX;Li BK;Fang JH;Zhuang SM
转化生长因子-β（TGF -β）/SMAD信号通路的异常激活在肝细胞癌（HCC）中经常被观察到。长链非编码RNA（lncRNA）是否调节TGF -β/SMAD信号在很大程度上仍然未知。在此，我们鉴定出一种在肝细胞癌中上调且由TGF -β转录诱导的致癌lncRNA（命名为lnc - UTGF，即由TGF -β上调的lncRNA）。在TGF -β刺激下，SMAD2/3结合到lnc - UTGF启动子上并激活lnc - UTGF的表达。反过来，过表达lnc - UTGF会增强TGF -β/SMAD信号，而沉默lnc - UTGF则会抑制该信号。机制研究表明，lnc - UTGF通过互补碱基配对与SMAD2和SMAD4的mRNA相互作用，导致SMAD2/4 mRNA的稳定性增强。这些数据表明存在一种新的TGF -β/SMAD/lnc - UTGF正反馈回路。随后的功能获得和缺失分析显示，lnc - UTGF促进肝癌细胞的迁移和侵袭，并且通过抑制SMAD2/4表达或突变lnc - UTGF中的SMAD2/4结合位点，lnc - UTGF的这种作用会减弱。利用小鼠模型的研究进一步证实，沉默lnc - UTGF可抑制肝癌异种移植物在体内的转移，而异位表达lnc - UTGF则会增强转移。在异种移植物中，lnc - UTGF水平与SMAD2/4水平呈正相关。一致地，我们在人类肝细胞癌中检测到lnc - UTGF的上调与SMAD2、SMAD4及其转移效应因子SNAIL1的增加相关。并且高lnc - UTGF水平还与转移潜能增强、TNM分期进展以及无复发生存期更差显著相关。结论：存在一个由lnc - UTGF介导的TGF -β信号正反馈环，其失调促进肝癌转移。这些发现可能为肝细胞癌转移提供一个新的治疗靶点。
Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma (HCC). Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown. Here, we identified an oncogenic lncRNA that was upregulated in HCC and was transcriptionally induced by TGF-β (named lnc-UTGF, lncRNA upregulated by TGF-β). Upon TGF-β stimulation, SMAD2/3 bound to the lnc-UTGF promoter and activated lnc-UTGF expression. In turn, the TGF-β/SMAD signaling was augmented by overexpressing lnc-UTGF, but was inhibited by silencing lnc-UTGF. Mechanism investigations revealed that lnc-UTGF interacted with the mRNAs of SMAD2 and SMAD4 via complementary base-pairing, resulting in enhanced stability of SMAD2/4 mRNAs. These data suggest a novel TGF-β/SMAD/lnc-UTGF positive feedback circuitry. Subsequent gain- and loss-of-function analyses disclosed that lnc-UTGF promoted the migration and invasion of hepatoma cells, and this effect of lnc-UTGF was attenuated by repressing SMAD2/4 expression or by mutating the SMAD2/4-binding sites in lnc-UTGF. Studies using mouse models further confirmed that in vivo metastasis of hepatoma xenografts was inhibited by silencing lnc-UTGF, but was enhanced by ectopic expression of lnc-UTGF. The lnc-UTGF level was positively correlated with the SMAD2/4 levels in xenografts. Consistently, we detected an association of lnc-UTGF upregulation with increase of SMAD2, SMAD4, and their metastasis effector SNAIL1 in human HCC. And high lnc-UTGF level was also significantly associated with enhanced metastasis potential, advanced TNM stages, and worse recurrence-free survival. Conclusion: there exists a lnc-UTGF-mediated positive feedback loop of the TGF-β signaling and its deregulation promotes hepatoma metastasis. These findings may provide a new therapeutic target for HCC metastasis.
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影响因子：
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作者：
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