CircHIF1A regulated by FUS accelerates triple-negative breast cancer progression by modulating NFIB expression and translocation
CircHIF1A regulated by FUS accelerates triple-negative breast cancer progression by modulating NFIB expression and translocation
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FUS 调控的 CircHIF1A 通过调节 NFIB 表达和易位加速三阴性乳腺癌进展
DOI：
10.1038/s41388-021-01739-z
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发表时间：
2021-03-13
期刊：
影响因子：
8
通讯作者：
Yang, Qifeng
中科院分区：
文献类型：
--
作者：
Chen, Tong;Wang, Xiaolong;Yang, Qifeng
越来越多的证据表明，环状RNA(CircRNAs)在人类癌症的发生和发展中起着关键作用。然而，CircRNAs在三阴性乳腺癌(TNBC)中的生物学功能和潜在机制仍有待研究。在我们目前的研究中，我们发现HIF1A附近的新的CircRNA在乳腺癌组织中显著过表达，并且它与转移、预后不良和TNBC亚型有关。通过功能获得和功能丧失实验，研究了CircHIF1A在TNBC中的生物学作用。在体内外，过表达CircHIF1A可显著促进TNBC的生长和转移，而下调CircHIF1A则起到相反的作用。机制上，HIF1A通过转录后和翻译后修饰调控NFIB的表达和转位，激活AKT/STAT3信号通路，抑制P21。RNA结合蛋白FUS通过与其侧翼内含子相互作用来调控CircHIF1A的生物发生，FUS受NFIB转录调控，从而形成CircHIF1A/NFIB/FUS正反馈环。此外，HIF1A可被包装成外切体，并在乳腺癌患者的血浆中上调。我们的研究结果表明，CircHIF1A通过一个正反馈环在TNBC的生长和转移中起着关键作用，CircHIF1A有望成为乳腺癌诊断的生物标志物和TNBC治疗的潜在靶点。
Emerging evidence has demonstrated that circular RNAs (circRNAs) play critical roles in the development and progression of human cancer. However, the biological functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) remain to be investigated. In our present study, we found that the novel circRNA circHIF1A was significantly overexpressed in breast cancer tissues and that it was associated with metastasis, poor prognosis, and the TNBC subtype. Gain- and loss-of-function experiments were conducted to investigate the biological roles of circHIF1A in TNBC. Overexpression of circHIF1A significantly promoted TNBC growth and metastasis in vitro and in vivo, while knockdown of circHIF1A exerted the opposite effects. Mechanistically, circHIF1A modulated the expression and translocation of NFIB through posttranscriptional and posttranslational modifications, resulting in the activation of the AKT/STAT3 signaling pathway and inhibition of P21. The RNA binding protein FUS could regulate the biogenesis of circHIF1A by interacting with the flanking intron, and FUS was transcriptionally regulated by NFIB, thus forming the circHIF1A/NFIB/FUS positive feedback loop. Moreover, circHIF1A could be packaged into exosomes and was upregulated in the plasma of breast cancer patients. Our findings indicated that circHIF1A played a critical role in the growth and metastasis of TNBC via a positive feedback loop and that circHIF1A could be a promising biomarker for breast cancer diagnosis and a potential therapeutic target for TNBC treatment.