Breast Disease Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
Department of Breast Surgery, Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, China.
Clin Transl Med. 2024 Aug;14(8):e1763. doi: 10.1002/ctm2.1763.
Breast cancer (BC) is one of the most prevalent malignant tumours that threatens women health worldwide. It has been reported that circular RNAs (circRNAs) play an important role in regulating tumour progression and tumour microenvironment (TME) remodelling.
Differentially expression characteristics and immune correlations of circRNAs in BC were verified using high-throughput sequencing and bioinformatic analysis. Exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. The biological function of circ-0100519 in BC development was demonstrated both in vitro and in vivo. Western blotting, RNA pull-down, RNA immunoprecipitation, flow cytometry, and luciferase reporter were conducted to investigate the underlying mechanism.
Circ-0100519 was significant abundant in BC tumour tissues and related to poor prognosis. It can be encapsulated into secreted exosomes, thereby promoting BC cell invasion and metastasis via inducing M2-like macrophages polarisation.Mechanistically, circ-0100519 acted as a scaffold to enhance the interaction between the deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) and nuclear factor-like 2 (NRF2) in macrophages, inducing the USP7-mediated deubiquitination of NRF2. Additionally, HIF-1α could function as an upstream effector to enhance circ-0100519 transcription.
Our study revealed that exosomal circ-0100519 is a potential biomarker for BC diagnosis and prognosis, and the HIF-1α inhibitor PX-478 may provide a therapeutic target for BC.
乳腺癌（BC）是全球范围内威胁女性健康的最常见恶性肿瘤之一。据报道，环状 RNA（circRNA）在调节肿瘤进展和肿瘤微环境（TME）重塑方面发挥着重要作用。
使用高通量测序和生物信息学分析验证了 BC 中 circRNA 的差异表达特征和免疫相关性。使用纳米颗粒透射电子显微镜和追踪分析对 exosomes 进行了表征。通过体外和体内实验证实了 circ-0100519 在 BC 发展中的生物学功能。通过 Western blot、RNA 下拉、RNA 免疫沉淀、流式细胞术和荧光素酶报告基因检测等方法研究了其潜在的作用机制。
circ-0100519 在 BC 肿瘤组织中丰度显著上调，与预后不良相关。它可以被包裹到分泌的 exosomes 中，从而通过诱导 M2 样巨噬细胞极化来促进 BC 细胞的侵袭和转移。机制上，circ-0100519 作为支架增强了巨噬细胞中去泛素化酶泛素特异性蛋白酶 7（USP7）和核因子样 2（NRF2）之间的相互作用，诱导 USP7 介导的 NRF2 去泛素化。此外，HIF-1α 可以作为上游效应因子增强 circ-0100519 的转录。
本研究表明，外泌体 circ-0100519 是 BC 诊断和预后的潜在生物标志物，HIF-1α 抑制剂 PX-478 可能为 BC 提供治疗靶点。
