HNF4A-AS1通过促进PCBP2的泛素调节性降解和抑制ARG2 mRNA的稳定性，抑制肝细胞癌的进展

HNF4A-AS1 inhibits the progression of hepatocellular carcinoma by promoting the ubiquitin-modulated degradation of PCBP2 and suppressing the stability of ARG2 mRNA

International Journal of Biological Sciences

影响因子:10

分区:生物学1区 Top / 生化与分子生物学2区

发表日期:2024

作者: Wenbo Jia, Liang Yu, Bin Xu, Yanzhi Feng, Jinyi Wang, Deming Zhu, Chao Xu, Litao Liang, Yongping Zhou, Lianbao Kong, Wenzhou Ding

DOI: 10.7150/ijbs.95276

摘要

肝细胞癌（HCC）是一种高度侵袭性的恶性肿瘤，预后较差。大量研究揭示了长非编码RNA（lncRNAs）在肿瘤发展调控中的重要作用。本研究利用高通量测序分析了三对HCC组织及其对应的非癌组织（NATs）中的lncRNA表达水平。通过定量实时聚合酶链反应（qRT-PCR）和临床病理分析发现，HNF4A-AS1在HCC组织中表达下调，其表达水平与HCC患者的预后呈正相关。后续的体外和体内功能研究表明，HNF4A-AS1抑制HCC细胞的增殖、侵袭和干性。机制上，HNF4A-AS1通过特定片段（491-672 nt）与PCBP2的KH3结构域发生物理相互作用，促进AIP4介导的PCBP2的泛素化及其降解。此外，HNF4A-AS1通过调控PCBP2，影响ARG2 mRNA的稳定性，从而影响HCC的恶性表型。总体而言，我们的研究在临床环境中显示HNF4A-AS1表达降低与患者预后呈正相关。HNF4A-AS1通过促进PCBP2的泛素调节性降解，抑制ARG2 mRNA的稳定性，从而抑制HCC的进展，具有潜在的治疗应用价值。

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent in vitro and in vivo functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.