HNF4A-AS1通过促进PCBP2的泛素调节降解并抑制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
影响因子:10.00000
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
摘要
肝细胞癌（HCC）是一种高度侵略性的恶性肿瘤，预后较差。广泛的研究揭示了长期非编码RNA（LNCRNA）在肿瘤发育的调节中的重要作用。在这项研究中，使用高通量测序分析来评估三对HCC组织中的LNCRNA的表达水平及其相应的非癌组织。通过定量的实时聚合酶链反应（QRT-PCR）分析和临床病理分析，发现HNF4A-AS1在HCC组织中被下调。此外，发现其表达水平与HCC患者的预后正相关。随后的体外和体内功能研究表明，HNF4A-AS1抑制了HCC细胞的增殖，浸润和干性。从机械上讲，观察到HNF4A-AS1通过特定段（491-672 NT）与PCBP2的KH3域进行物理相互作用。这种相互作用促进了通过AIP4募集PCBP2，从而导致PCBP2的泛素化和随后降解。此外，发现HNF4A-AS1通过调节PCBP2来调节AGR2 mRNA的稳定性，从而影响HCC的恶性表型。总体而言，我们的研究表明，在临床环境中，HNF4A-AS1表达降低与HCC患者的预后之间存在正相关。 HNF4A-AS1可以通过促进PCBP2的泛素调节降解来抑制ARG2 mRNA的稳定性，从而抑制HCC的进展。 HNF4A-AS1可以作为HCC的潜在治疗靶点。
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.