Tang Lingyu, Deng Xuan, Guan Ming, Zhong Liang
Department of Gastroenterology and Endoscopy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Department of Laboratory Medicine, Huashan Hospital Fudan University, Shanghai, 200040, China.
Noncoding RNA Res. 2025 Apr 8;13:15-28. doi: 10.1016/j.ncrna.2025.04.003. eCollection 2025 Aug.
Chemotherapeutic efficacy in colorectal cancer (CRC) is significantly hindered by the development of drug resistance. Emerging evidence indicates that circular RNAs (circRNAs) play pivotal roles in various cancer-related biological processes. Nonetheless, the specific role of circRNAs in oxaliplatin resistance in CRC remains largely unexplored. In this study, hsa_circ_0076691 (circ76691) overexpression was observed in the oxaliplatin-resistant CRC group and could predict poor prognosis. Functional analyses revealed that circ76691 attenuates oxaliplatin-induced apoptosis both and , thereby contributing to enhanced oxaliplatin resistance. Mechanistically, circ76691 transcriptionally downregulates miR-589-3p expression and acts as a molecular sponge for miR-589-3p, sequestering it from its downstream targets. Notably, fibroblast growth factor 9 (FGF9), identified as a downstream inhibitory target of miR-589-3p, is subsequently upregulated due to circ76691 activity. Furthermore, circ76691 expression is transcriptionally induced by USF1 through direct binding to its promoter region. Collectively, these findings elucidate the USF1/circ76691/miR-589-3p/FGF9 axis in inhibiting oxaliplatin-induced apoptosis, suggesting circ76691 as a potential therapeutic target to enhance the efficacy of platinum-based therapy.
结直肠癌（CRC）中的化疗疗效因耐药性的产生而受到显著阻碍。新出现的证据表明，环状RNA（circRNA）在各种癌症相关的生物学过程中发挥着关键作用。然而，circRNA在CRC对奥沙利铂耐药中的具体作用在很大程度上仍未得到探索。在本研究中，在奥沙利铂耐药的CRC组中观察到hsa_circ_0076691（circ76691）过表达，并且其可预测不良预后。功能分析显示，circ76691在体内和体外均减弱奥沙利铂诱导的细胞凋亡，从而导致奥沙利铂耐药性增强。机制上，circ76691转录下调miR-589-3p的表达，并作为miR-589-3p的分子海绵，将其与其下游靶标隔离。值得注意的是，成纤维细胞生长因子9（FGF9）被鉴定为miR-589-3p的下游抑制靶标，随后由于circ76691的作用而上调。此外，circ76691的表达由USF1通过直接结合其启动子区域进行转录诱导。总的来说，这些发现阐明了USF1/circ76691/miR-589-3p/FGF9轴在抑制奥沙利铂诱导的细胞凋亡中的作用，表明circ76691作为增强铂类疗法疗效的潜在治疗靶点。
