Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Oncogene. 2021 Apr;40(15):2756-2771. doi: 10.1038/s41388-021-01739-z. Epub 2021 Mar 13.
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.
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发挥着关键作用。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。在本研究中，我们发现新型环状 RNA circHIF1A 在乳腺癌组织中显著过表达，并且与转移、预后不良和 TNBC 亚型有关。通过增益和缺失功能实验研究了 circHIF1A 在 TNBC 中的生物学作用。circHIF1A 的过表达显著促进了 TNBC 在体外和体内的生长和转移，而 circHIF1A 的敲低则产生了相反的效果。机制上，circHIF1A 通过转录后和翻译后修饰调节 NFIB 的表达和易位，从而激活 AKT/STAT3 信号通路并抑制 P21。RNA 结合蛋白 FUS 可以通过与侧翼内含子相互作用来调节 circHIF1A 的生物发生，而 FUS 则受 NFIB 的转录调控，从而形成 circHIF1A/NFIB/FUS 正反馈环。此外，circHIF1A 可以被包裹在外泌体中，并在上皮性乳腺癌患者的血浆中上调。我们的研究结果表明，circHIF1A 通过正反馈环在 TNBC 的生长和转移中发挥着关键作用，并且 circHIF1A 可能是乳腺癌诊断的有前途的生物标志物，也是 TNBC 治疗的潜在治疗靶点。
