Liu Meiliang, Lai Mingshuang, Li Deyuan, Zhang Ruirui, Wang Lijun, Peng Wenyi, Yang Jialei, He Wanting, Sheng Yonghong, Xiao Suyang, Nan Aruo, Zeng Xiaoyun
Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, China.
Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China.
Cancer Sci. 2023 Oct;114(10):3884-3899. doi: 10.1111/cas.15906. Epub 2023 Aug 7.
Accumulating evidence indicates that circular RNAs (circRNAs) are inextricably linked to cancer development. However, the function and mechanism of nucleus-localized circRNAs in hepatocellular carcinoma (HCC) still require investigation. Here, qRT-PCR and receiver-operating characteristic curve were used to detect the expression and diagnostic potential of circSLC39A5 for HCC. The biological function of circSLC39A5 in HCC was investigated in vitro and in vivo. Nucleoplasmic separation assay, fluorescence in situ hybridization, RNA pulldown, RNA immunoprecipitation, the HDOCK Server, the NucleicNet Webserver, crosslinking-immunoprecipitation, MG132 treatment, and chromatin immunoprecipitation were utilized to explore the potential molecular mechanism of circSLC39A5 in HCC. The results showed that circSLC39A5 was downregulated in both HCC tissues and plasma and was associated with satellite nodules and lymph node metastasis/vascular invasion. CircSLC39A5 was stably expressed in plasma samples under different storage conditions, showing good diagnostic potential for HCC (AUC = 0.915). CircSLC39A5 inhibited proliferation, migration, and invasion, facilitated the apoptosis of HCC cells, and was associated with low expression of Ki67 and CD34. Remarkably, circSLC39A5 is mainly localized in the nucleus and binds to the transcription factor signal transducer and activator of transcription 1 (STAT1), affecting its stabilization and expression. STAT1 binds to the promoter of thymine DNA glycosylase (TDG). Overexpression of circSLC39A5 elevates TDG expression and reverses the increase of proliferating cell nuclear antigen (PCNA) expression and the overactive cell proliferation caused by TDG silencing. Our findings uncovered a novel plasma circRNA, circSLC39A5, which may be a potential circulating diagnostic marker for HCC, and the mechanism by which nucleus-localized circSLC39A5 exerts a transcriptional regulatory role in HCC by affecting STAT1/TDG/PCNA provides new insights into the mechanism of circRNAs.
越来越多的证据表明，环状RNA（circRNA）与癌症发展密切相关。然而，细胞核定位的circRNA在肝细胞癌（HCC）中的功能和机制仍有待研究。在此，采用qRT-PCR和受试者工作特征曲线检测circSLC39A5在HCC中的表达及诊断潜力。在体外和体内研究了circSLC39A5在HCC中的生物学功能。利用核质分离试验、荧光原位杂交、RNA下拉、RNA免疫沉淀、HDOCK服务器、NucleicNet网络服务器、交联免疫沉淀、MG132处理和染色质免疫沉淀，探讨circSLC39A5在HCC中的潜在分子机制。结果显示，circSLC39A5在HCC组织和血浆中均下调，且与卫星结节及淋巴结转移/血管侵犯相关。circSLC39A5在不同储存条件下的血浆样本中表达稳定，对HCC具有良好的诊断潜力（AUC = 0.915）。circSLC39A5抑制HCC细胞的增殖、迁移和侵袭，促进其凋亡，并与Ki67和CD3呈低表达相关。值得注意的是，circSLC39A5主要定位于细胞核，并与转录因子信号转导和转录激活因子1（STAT1）结合，影响其稳定性和表达。STAT1与胸腺嘧啶DNA糖基化酶（TDG）的启动子结合。circSLC39A5的过表达提高了TDG的表达，并逆转了由TDG沉默导致的增殖细胞核抗原（PCNA）表达增加和细胞增殖过度活跃的现象。我们的研究发现了一种新的血浆circRNA，即circSLC39A5，它可能是HCC潜在的循环诊断标志物，并且细胞核定位的circSLC39A5通过影响STAT1/TDG/PCNA在HCC中发挥转录调控作用的机制为circRNA的作用机制提供了新的见解。
