Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
Department of Breast Surgery, The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, China.
J Exp Clin Cancer Res. 2023 Jun 1;42(1):138. doi: 10.1186/s13046-023-02701-5.
Breast cancer (BC) negatively impacts the health of women worldwide. Circular RNAs (circRNAs) are a group of endogenous RNAs considered essential regulatory factor in BC tumorigenesis and progression. However, the underlying molecular mechanisms of circRNAs remain unclear.
Expression levels of circPAPD4, miR-1269a, CREBZF, and ADAR1 in BC cell lines and tissues were measured using bioinformatics analysis, RT-qPCR, ISH, and IHC. Cell proliferation and apoptosis were measured using CCK8, EdU staining, flow cytometry, and TUNEL assays. Pearson correlation analysis, RNA pull-down, dual-luciferase reporter, and co-immunoprecipitation assays were used to explore the correlation among circPAPD4, miR-1269a, CREBZF, STAT3, and ADAR1. Effects of circPAPD4 overexpression on tumor progression were investigated using in vivo assays. Moreover, CREBZF mRNA delivered by polymeric nanoparticles (CREBZF-mRNA-NPs) was used to examine application value of our findings.
CircPAPD4 expression was low in BC tissues and cells. Functionally, circPAPD4 inhibited proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, circPAPD4 biogenesis was regulated by ADAR1. And circPAPD4 promoted CREBZF expression by competitively binding to miR-1269a. More importantly, CREBZF promoted circPAPD4 expression by suppressing STAT3 dimerization and ADAR1 expression, revealing a novel positive feedback loop that curbed BC progression. Systematic delivery of CREBZF-mRNA-NPs effectively induced CREBZF expression and activated the positive feedback loop of circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1, which might suppress BC progression in vitro and in vivo.
Our findings firstly illustrated that circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1 positive feedback loop mediated BC progression, and delivering CREBZF mRNA nanoparticles suppressed BC progression in vitro and in vivo, which might provide novel insights into therapeutic strategies for breast cancer.
乳腺癌（BC）对全球女性的健康造成负面影响。环状 RNA（circRNA）是一组内源性 RNA，被认为是 BC 肿瘤发生和发展的重要调节因子。然而，circRNA 的潜在分子机制尚不清楚。
使用生物信息学分析、RT-qPCR、ISH 和 IHC 测量 BC 细胞系和组织中 circPAPD4、miR-1269a、CREBZF 和 ADAR1 的表达水平。使用 CCK8、EdU 染色、流式细胞术和 TUNEL 测定法测量细胞增殖和凋亡。使用 Pearson 相关性分析、RNA 下拉、双荧光素酶报告基因和共免疫沉淀测定法来探索 circPAPD4、miR-1269a、CREBZF、STAT3 和 ADAR1 之间的相关性。使用体内实验研究 circPAPD4 过表达对肿瘤进展的影响。此外，使用聚合物纳米颗粒（CREBZF-mRNA-NPs）递送 CREBZF mRNA，以检验我们研究结果的应用价值。
circPAPD4 在 BC 组织和细胞中的表达水平较低。功能上，circPAPD4 抑制体外和体内的增殖并促进凋亡。机制上，circPAPD4 的生物发生受 ADAR1 调节。circPAPD4 通过竞争性结合 miR-1269a 促进 CREBZF 表达。更重要的是，CREBZF 通过抑制 STAT3 二聚化和 ADAR1 表达促进 circPAPD4 表达，揭示了一个新的正反馈环，抑制了 BC 的进展。系统递送 CREBZF-mRNA-NPs 可有效诱导 CREBZF 表达并激活 circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1 的正反馈环，可能在体外和体内抑制 BC 的进展。
我们的研究结果首次表明，circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1 正反馈环介导 BC 进展，递送 CREBZF mRNA 纳米颗粒可在体外和体内抑制 BC 进展，为乳腺癌的治疗策略提供了新的见解。
