Wan Meiling, Wang Yonghong, Liu Xiaoling, Li Yaling, Deng Cunliang, Sun Changfeng
Department of Infectious Diseases, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
Laboratory of Infection and Immunity, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
Heliyon. 2024 Dec 31;11(1):e41594. doi: 10.1016/j.heliyon.2024.e41594. eCollection 2025 Jan 15.
Hepatocellular carcinoma (HCC) is a significant global health concern, with chronic hepatitis B virus (HBV) infection being a major contributor. Understanding the mechanisms of HBV-associated HCC is crucial to improving the prognosis and developing effective treatments.
HBV-associated HCC datasets (GSE19665, GSE121248, GSE55092, GSE94660, and TCGA-LIHC) acquired from public databases were mined to identify key driver genes by differentially expressed gene analysis, weighted gene co-expression network analysis (WGCNA), followed by protein-protein interaction network analysis, Lasso-Cox regression analysis, and randomforestSRC algorithm. Then, in vitro experiments including CCK-8 assay, wound healing, and Transwell assay were performed to explore the functions and mechanisms.
RAD51AP1 was identified as a specific key gene linked to the progression of HBV-associated HCC. High expression of RAD51AP1 was associated with worse overall survival (OS) in patients with HBV-associated HCC, but not in patients with non-HBV-associated HCC. Mechanistically, RAD51AP1 forms a potential ceRNA axis with LINC01419 and miR-8070, where LINC01419 acts as a molecular sponge for miR-8070 to upregulate RAD51AP1. HBV infection can enhance the LINC01419/miR-8070/RAD51AP1 axis, and LINC01419 overexpression conversely promotes HBV replication. The ceRNA axis and HBV synergistically promote the proliferation and metastasis of HBV-associated HCC cells. Furthermore, LINC01419 or RAD51AP1 knockdown, and miR-8070 overexpression in HepG2.2.15 cells significantly attenuated the Wnt/β-catenin signaling.
The LINC01419/miR-8070/RAD51AP1 axis promotes the HBV-associated HCC progression through an HBV-boosted positive feedback loop and Wnt/β-catenin signaling. These findings provide novel insights into the underlying mechanisms and may offer potential diagnostic and therapeutic targets in HBV-associated HCC.
肝细胞癌（HCC）是一个重大的全球健康问题，慢性乙型肝炎病毒（HBV）感染是主要促成因素。了解HBV相关HCC的发病机制对于改善预后和开发有效治疗方法至关重要。
从公共数据库获取HBV相关HCC数据集（GSE19665、GSE121248、GSE55092、GSE94660和TCGA-LIHC），通过差异表达基因分析、加权基因共表达网络分析（WGCNA），随后进行蛋白质-蛋白质相互作用网络分析、套索-考克斯回归分析和随机森林SRC算法来识别关键驱动基因。然后，进行包括CCK-8测定、伤口愈合和Transwell测定在内的体外实验，以探索其功能和机制。
RAD51AP1被确定为与HBV相关HCC进展相关的特定关键基因。RAD51AP1的高表达与HBV相关HCC患者较差的总生存期（OS）相关，但与非HBV相关HCC患者无关。从机制上讲，RAD51AP1与LINC01419和miR-8070形成潜在的ceRNA轴，其中LINC01419作为miR-8070的分子海绵上调RAD51AP1。HBV感染可增强LINC01419/miR-8070/RAD51AP1轴，而LINC01419的过表达反过来促进HBV复制。ceRNA轴和HBV协同促进HBV相关HCC细胞的增殖和转移。此外，在HepG2.2.15细胞中敲低LINC01419或RAD51AP1以及过表达miR-8070可显著减弱Wnt/β-连环蛋白信号传导。
LINC01419/miR-8070/RAD51AP1轴通过HBV增强的正反馈回路和Wnt/β-连环蛋白信号传导促进HBV相关HCC进展。这些发现为潜在机制提供了新见解，并可能为HBV相关HCC提供潜在的诊断和治疗靶点。
