环状 RNA 结合因子 8 通过 miR-217/NAP1L1 轴促进肝细胞癌的进展，并通过外泌体介导的转移诱导血管生成和瑞戈非尼耐药。
CircDCAF8 promotes the progression of hepatocellular carcinoma through miR-217/NAP1L1 Axis, and induces angiogenesis and regorafenib resistance via exosome-mediated transfer.
机构信息
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu Province, China.
出版信息
J Transl Med. 2024 May 30;22(1):517. doi: 10.1186/s12967-024-05233-4.
BACKGROUND
Circular RNAs (circRNAs), which are a new type of single-stranded circular RNA, have significant involvement in progression of many diseases, including tumors. Currently, multiple circRNAs have been identified in hepatocellular carcinoma (HCC). Our study aims to investigate the function and mechanism of circDCAF8 in HCC.
METHODS
The expression of circDCAF8 (hsa_circ_0014879) in HCC and para-carcinoma tissue samples was determined using quantitative real-time polymerase chain reaction (qRT-PCR). The biological function of circDCAF8 in HCC was confirmed by experiments conducted both in vitro and in vivo. And the relationship between circDCAF8, miR-217 and NAP1L1 was predicted by database and verified using qRT-PCR, RNA-binding protein immunoprecipitation (RIP) and dual-luciferase reporter assays. Exosomes isolated from HCC cells were utilized to assess the connection of exosomal circDCAF8 with HCC angiogenesis and regorafenib resistance.
RESULTS
CircDCAF8 is upregulated in HCC tissues and cell lines, and is linked to an unfavourable prognosis for HCC patients. Functionally, circDCAF8 was proved to facilitate proliferation, migration, invasion and Epithelial-Mesenchymal Transformation (EMT) in HCC cells. Animal examinations also validated the tumor-promoting characteristics of circDCAF8 on HCC. Besides, exosomal circDCAF8 promoted angiogenesis in HUVECs. Mechanistically, circDCAF8 interacted with miR-217 and NAP1L1 was a downstream protein of miR-217. CircDCAF8 promoted NAP1L1 expression by sponging miR-217. In addition, exosomes may transfer circDCAF8 from regorafenib-resistant HCC cells to sensitive cells, where it would confer a resistant phenotype.
CONCLUSION
CircDCAF8 facilitates HCC proliferation and metastasis via the miR-217/NAP1L1 axis. Meanwhile, circDCAF8 can promote angiogenesis and drive resistance to regorafenib, making it a viable therapeutic target for HCC patients.
背景
环状 RNA（circRNAs）是一种新型的单链环状 RNA，在许多疾病的进展中都有重要作用，包括肿瘤。目前，在肝细胞癌（HCC）中已经鉴定出多种 circRNAs。我们的研究旨在探讨 circDCAF8 在 HCC 中的功能和机制。
方法
采用实时定量聚合酶链反应（qRT-PCR）检测 HCC 及癌旁组织样本中 circDCAF8（hsa_circ_0014879）的表达。通过体外和体内实验证实 circDCAF8 在 HCC 中的生物学功能。通过数据库预测 circDCAF8、miR-217 和 NAP1L1 之间的关系，并通过 qRT-PCR、RNA 结合蛋白免疫沉淀（RIP）和双荧光素酶报告基因检测进行验证。利用 HCC 细胞分离的外泌体来评估外泌体 circDCAF8 与 HCC 血管生成和regorafenib 耐药的关系。
结果
circDCAF8 在 HCC 组织和细胞系中上调，并与 HCC 患者的不良预后相关。功能上，circDCAF8 被证明可促进 HCC 细胞的增殖、迁移、侵袭和上皮-间充质转化（EMT）。动物实验也验证了 circDCAF8 对 HCC 的促瘤作用。此外，外泌体 circDCAF8 促进了 HUVECs 的血管生成。机制上，circDCAF8 与 miR-217 相互作用，NAP1L1 是 miR-217 的下游蛋白。circDCAF8 通过海绵吸附 miR-217 促进 NAP1L1 表达。此外，外泌体可能将 circDCAF8 从耐药 HCC 细胞转移到敏感细胞中，从而赋予其耐药表型。
结论
circDCAF8 通过 miR-217/NAP1L1 轴促进 HCC 的增殖和转移。同时，circDCAF8 可促进血管生成，并导致对 regorafenib 的耐药性，使其成为 HCC 患者的一个可行的治疗靶点。
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