Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, 250033, China.
Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, China.
Cell Death Dis. 2023 Jan 25;14(1):59. doi: 10.1038/s41419-023-05598-2.
The regulatory role of circRNAs in cancer metastasis has become a focused issue in recent years. To date, however, the discovery of novel functional circRNAs and their regulatory mechanisms via binding with RBPs in bladder cancer (BC) are still lacking. Here, we screened out circSLC38A1 based on our sequencing data and followed validation with clinical tissue samples and cell lines. Functional assays showed that circSLC38A1 promoted BC cell invasion in vitro and lung metastasis of mice in vivo. By conducting RNA pull-down, mass spectrum, and RIP assays, circSLC38A1 was found to interact with Interleukin enhancer-binding factor 3 (ILF3), and stabilize ILF3 protein via modulating the ubiquitination process. By integrating our CUT&Tag-seq and RNA-seq data, TGF-β2 was identified as the functional target of the circSLC38A1-ILF3 complex. In addition, m6A methylation was enriched in circSLC38A1 and contributed to its upregulation. Clinically, circSLC38A1 was identified in serum exosomes of BC patients and could distinguish BC patients from healthy individuals with a diagnostic accuracy of 0.878. Thus, our study revealed an essential role and clinical significance of circSLC38A1 in BC via activating the transcription of TGF-β2 in an ILF3-dependent manner, extending the understanding of the importance of circRNA-mediated transcriptional regulation in BC metastasis.
环状 RNA （circRNAs）在癌症转移中的调控作用近年来成为研究热点。然而，迄今为止，膀胱癌（BC）中新型功能性 circRNAs 的发现及其与 RBPs 结合的调控机制仍有待探索。本研究基于测序数据筛选出 circSLC38A1，并通过临床组织样本和细胞系进行验证。功能实验表明，circSLC38A1 促进了 BC 细胞的体外侵袭和体内肺转移。通过 RNA 下拉、质谱和 RIP 实验，发现 circSLC38A1 与白细胞介素增强结合因子 3（ILF3）相互作用，并通过调节泛素化过程稳定 ILF3 蛋白。通过整合我们的 CUT&Tag-seq 和 RNA-seq 数据，鉴定出 TGF-β2 是 circSLC38A1-ILF3 复合物的功能靶标。此外，m6A 甲基化在 circSLC38A1 中富集，并促进其上调。临床研究发现，BC 患者血清外泌体中存在 circSLC38A1，可将 BC 患者与健康个体区分开来，诊断准确率为 0.878。因此，本研究通过 ILF3 依赖性方式激活 TGF-β2 的转录，揭示了 circSLC38A1 在 BC 中的重要作用和临床意义，扩展了我们对 circRNA 介导的转录调控在 BC 转移中的重要性的认识。
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