An Jiayue, Sun Weimiao, Ti Chenhui, Mu Yulong, Yin Baohui, Wang Qin, Zhang Xia, Liang Yan, Sun Hongfang, Xie Shuyang, Li Youjie
The Second Medical College of Binzhou Medical University, Yantai, Shandong, People's Republic of China.
Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
FASEB J. 2025 Sep 15;39(17):e71002. doi: 10.1096/fj.202501444RR.
Among lung cancers, non-small-cell lung cancer (NSCLC) is the most common type. Evidence demonstrates that abnormal expression of circular RNAs (circRNAs) is associated with cancer progression through interactions with RNA-binding proteins (RBPs). Therefore, further elucidation of the role of circular RNAs may provide new therapeutic targets for NSCLC patients. This study identified a novel circRNA, circHMGCS1 (hsa_circ_0072387), using circRNA microarrays. Validation and characterization of circHMGCS1 were performed by Sanger sequencing and RNase R treatment. CCK-8 and Transwell assays were used to determine the function of circHMGCS1 in cell proliferation and migration. The interaction between circHMGCS1 and human antigen R (HuR) protein was verified by RNA pull-down and RNA immunoprecipitation (RIP) assays. The effect of HuR on the stability of splicing factor proline- and glutamine-rich (SFPQ) mRNA was verified by dual-luciferase reporter gene assay and actinomycin D treatment. We found that circHMGCS1 was upregulated in NSCLC cells and tissues. Mechanistically, circHMGCS1 binds to HuR, and its high expression stabilizes HuR by inhibiting its ubiquitin-mediated degradation. HuR was shown to mediate the stability of SFPQ mRNA and promote the progression of NSCLC. RNA sequencing analysis indicated that SFPQ may inhibit apoptosis by suppressing tumor necrosis factor (TNF) signaling. This study revealed that circHMGCS1 contributes to NSCLC progression by stabilizing oncogenic HuR and promoting post-transcriptional upregulation of SFPQ, highlighting its potential as a diagnostic and prognostic biomarker for NSCLC.
在肺癌中，非小细胞肺癌（NSCLC）是最常见的类型。有证据表明，环状RNA（circRNA）的异常表达通过与RNA结合蛋白（RBP）相互作用而与癌症进展相关。因此，进一步阐明环状RNA的作用可能为NSCLC患者提供新的治疗靶点。本研究使用circRNA微阵列鉴定了一种新型circRNA，即circHMGCS1（hsa_circ_0072387）。通过Sanger测序和RNase R处理对circHMGCS1进行了验证和表征。采用CCK-8和Transwell实验来确定circHMGCS1在细胞增殖和迁移中的功能。通过RNA下拉和RNA免疫沉淀（RIP）实验验证了circHMGCS1与人抗原R（HuR）蛋白之间的相互作用。通过双荧光素酶报告基因实验和放线菌素D处理验证了HuR对富含脯氨酸和谷氨酰胺的剪接因子（SFPQ）mRNA稳定性的影响。我们发现circHMGCS1在NSCLC细胞和组织中上调。机制上，circHMGCS1与HuR结合，其高表达通过抑制HuR泛素介导的降解来使其稳定。研究表明，HuR介导SFPQ mRNA的稳定性并促进NSCLC的进展。RNA测序分析表明，SFPQ可能通过抑制肿瘤坏死因子（TNF）信号传导来抑制细胞凋亡。本研究揭示，circHMGCS1通过稳定致癌性HuR和促进SFPQ的转录后上调而促进NSCLC进展，突出了其作为NSCLC诊断和预后生物标志物的潜力。
