Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China.
The First Hospital of Jilin University, Changchun, 130021, China.
Cancer Lett. 2022 Sep 1;543:215781. doi: 10.1016/j.canlet.2022.215781. Epub 2022 Jun 7.
Triple-negative breast cancer (TNBC) is a rapidly recurring and highly metastatic malignancy with high heterogeneity and chemoradiotherapy resistance. Chronic unpredictable mild stress (CUMS) can induce the occurrence of tumors and enhance lymphatic infiltration and distant metastasis through direct interaction with the sympathetic nervous system; however, its relevance in TNBC is yet to be clarified. In this study, DARS-AS1, a newly reported CUMS-responsive lncRNA, was found to be enriched in TNBC clinical tumors and cells and positively correlated with late clinical stage in patients with TNBC. DARS-AS1 overexpression significantly enhanced the migration and invasion of TNBC tumors by inhibiting miR-129-2-3p and upregulated CDK1 to activate the NF-κB/STAT3 signaling pathway both in vitro and in vivo. Treatment with DARS-AS1 siRNA-loaded exosomes (EXOs) substantially slowed CUMS-induced TNBC cell growth and liver metastasis. Therefore, DARS-AS1 represents a potential therapeutic target for metastatic TNBC, and EXOs may serve as siRNA delivery carriers in clinical therapy.
三阴性乳腺癌（TNBC）是一种快速复发和高度转移性的恶性肿瘤，具有高度异质性和化疗放疗耐药性。慢性不可预测轻度应激（CUMS）可以通过与交感神经系统的直接相互作用诱导肿瘤的发生，并增强淋巴浸润和远处转移；然而，其在 TNBC 中的相关性尚不清楚。在这项研究中，一种新报道的 CUMS 反应性 lncRNA DARS-AS1 被发现富集在 TNBC 临床肿瘤和细胞中，并与 TNBC 患者的晚期临床分期呈正相关。DARS-AS1 的过表达通过抑制 miR-129-2-3p 并上调 CDK1 来激活 NF-κB/STAT3 信号通路，显著增强了 TNBC 肿瘤的迁移和侵袭，无论是在体外还是体内。用 DARS-AS1 siRNA 负载的外泌体（EXOs）治疗可显著减缓 CUMS 诱导的 TNBC 细胞生长和肝转移。因此，DARS-AS1 可能是转移性 TNBC 的潜在治疗靶点，EXOs 可能在临床治疗中作为 siRNA 传递载体。
