circRNA 在肝细胞癌 (HCC) 进展中的作用仍不清楚。通过生物信息学分析，CircPIAS1（circBase ID：hsa_circ_0007088）被确定在 HCC 病例中过度表达。本研究旨在探讨 circPIAS1 在 HCC 发展中的致癌特性和机制。进行功能分析以评估 circPIAS1 对 HCC 细胞增殖、迁移和铁死亡的影响。采用异种移植小鼠模型来评估 circPIAS1 对体内肿瘤生长和肺转移的影响。利用生物信息学分析、RNA 免疫沉淀和荧光素酶报告基因测定来阐明受 circPIAS1 影响的分子途径。使用 RNA Pulldown、荧光原位杂交 (FISH)、染色质免疫沉淀 (ChIP)、qPCR 和蛋白质印迹等其他技术来进一步探讨潜在机制。CircPIAS1 表达在 HCC 组织和细胞中升高。沉默 circPIAS1 可抑制体外和体内 HCC 细胞的增殖和迁移。从机械角度来看，circPIAS1 过表达通过与 miR-455-3p 竞争性结合来抑制铁死亡，导致核蛋白 1 (NUPR1) 上调。此外，NUPR1 促进 FTH1 转录，增强 HCC 细胞中铁的储存并赋予对铁死亡的抵抗力。使用 NUPR1 抑制剂 ZZW-115 治疗可逆转 circPIAS1 的促肿瘤作用，并使 HCC 细胞对乐伐替尼敏感。这项研究强调了 circPIAS1 通过调节铁死亡在 HCC 进展中的关键作用。靶向 circPIAS1/miR-455-3p/NUPR1/FTH1 调节轴可能代表一种有前途的 HCC 治疗策略。© 2024。作者。

The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development.Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms.CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib.This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.© 2024. The Author(s).