Long non-coding RNAs AC026904.1 and UCA1: a "one-two punch" for TGF-β-induced SNAI2 activation and epithelial-mesenchymal transition in breast cancer.
Long non-coding RNAs AC026904.1 and UCA1: a "one-two punch" for TGF-β-induced SNAI2 activation and epithelial-mesenchymal transition in breast cancer.
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长非编码 RNA AC026904.1 和 UCA1：乳腺癌中 TGF-β 诱导的 SNAI2 激活和上皮间质转化的“一两拳”
作者：
Li GY;Wang W;Sun JY;Xin B;Zhang X;Wang T;Zhang QF;Yao LB;Han H;Fan DM;Yang AG;Jia LT;Wang L
转化生长因子-β（Transforming growth factor-β，TGF-β）是肿瘤发生发展过程中上皮-间质转化（epithelial-mesenchymal transition，EMT）的主要诱导因子，主要通过激活SNAI 2/Slug等一系列多效性转录因子而发挥作用。然而，长链非编码RNA（lncRNA）参与TGF-β诱导的Slug活化和EMT仍然在很大程度上未知。方法：在这项研究中，我们使用微阵列分析比较TGF-β处理和未处理的乳腺癌细胞之间的lncRNA表达谱。然后，通过qPCR和Kaplan-Meier生存分析来研究lncRNA在乳腺癌中的临床意义。通过激光共聚焦显微镜、Western blotting、染色体构象捕获（3C）、染色质分离纯化（ChIRP）、ChIP、荧光素酶报告基因分析和transwell迁移实验等方法，分析其促进EMT的分子机制和体外EMT效应。最后，通过生物发光成像和苏木精和伊红（H&E）染色评价体内促转移作用。结果如下：我们观察到TGF-β诱导乳腺癌细胞lncRNA水平的全基因组变化，其中AC026904.1和UCA 1在转移性乳腺癌中高表达，与预后不良密切相关。机制研究表明，AC026904.1和UCA 1分别通过非经典和经典TGF-β途径上调。进一步的分析表明，AC026904.1在细胞核中起增强子RNA的作用，而UCA 1在细胞质中发挥竞争性内源RNA（ceRNA）活性。另外，这两种lncRNA的生物学功能集中在Slug的激活和维持上，构成了促进EMT和肿瘤转移的一对重拳。结论：这些发现首次揭示了AC026904.1和UCA 1可以在转录和转录后水平协同上调Slug表达，在TGF-β诱导的EMT中发挥关键作用。目前的工作提供了新的证据，lncRNA作为EMT的关键调节因子发挥作用，并有望成为转移性乳腺癌的新生物标志物和治疗靶点。
Transforming growth factor-β (TGF-β) has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) during cancer progression, mainly by activating a set of pleiotropic transcription factors including SNAI2/Slug. However, the involvement of long non-coding RNAs (lncRNAs) in TGF-β-induced Slug activation and EMT remains largely unknown. Methods: In this study, we used microarray analysis to compare lncRNA expression profiles between TGF-β treated and untreated breast cancer cells. Then, the clinical significance of lncRNAs in breast cancer was investigated by qPCR and Kaplan-Meier survival analysis. The molecular mechanisms and EMT-promoting effects in vitro were analyzed by confocal laser microscopy, Western blotting, chromosome conformation capture (3C), chromatin isolation by RNA purification (ChIRP), ChIP, luciferase reporter assay and transwell migration assay. Lastly, the pro-metastatic effects in vivo were evaluated by bioluminescent imaging and hematoxylin and eosin (H&E) staining. Results: We observed that TGF-β induced genome-wide changes in lncRNA levels in breast cancer cells, among which AC026904.1 and UCA1 were highly expressed in metastatic breast cancer and closely associated with poor prognosis. Mechanistic study revealed that AC026904.1 and UCA1 were upregulated by non-canonical and canonical TGF-β pathways, respectively. Further analysis showed that AC026904.1 functions as an enhancer RNA in the nucleus, whereas UCA1 exerts a competitive endogenous RNA (ceRNA) activity in the cytoplasm. In addition, the biological functions of these two lncRNAs converged on the activation and maintenance of Slug, constituting a one-two punch in promoting EMT and tumor metastasis. Conclusion: These findings uncover for the first time that AC026904.1 and UCA1 could cooperatively upregulate Slug expression at both transcriptional and post-transcriptional levels, exerting critical roles in TGF-β-induced EMT. The present work provides new evidence that lncRNAs function as key regulators of EMT and hold great promise to be used as novel biomarkers and therapeutic targets for metastatic breast cancer.
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DOI：
10.1186/bcr1026
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jenkins DE;Hornig YS;Oei Y;Dusich J;Purchio T
通讯作者：
Purchio T
影响因子：
28.2
作者：
Karreth FA;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
56.9
作者：
Kapranov, Philipp;Cheng, Jill;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
影响因子：
4.8
作者：
Lu, X;Law, BK;Moses, HL
通讯作者：
Moses, HL
DOI：
10.1186/s13046-017-0518-0
发表时间：
2017-04-17
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Lu Z;Li Y;Wang J;Che Y;Sun S;Huang J;Chen Z;He J
通讯作者：
He J