Ding Ke, Liu Lei, Yong Wang, Sun Beicheng, Zhang Wenjie
Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Eur J Med Res. 2025 Jul 16;30(1):628. doi: 10.1186/s40001-025-02866-z.
Telomere maintenance mechanisms (TMMs) play a distinct role in the initiation and progression of hepatocellular carcinoma (HCC). However, the prognostic relevance of telomere maintenance (TM)-related genes in HCC remains largely unclear.
We integrated expression profiles of TM-related genes and corresponding clinicopathological data from public databases. Univariate analyses were performed to identify prognostic genes, and Cytoscape software was used to validate hub genes within the TM-related network. A novel prognostic signature was then constructed using the LASSO Cox regression algorithm. Finally, in vitro experiments were conducted to explore the functional roles of the key hub gene KPNA2 in telomere maintenance, tumor growth, and metastasis in HCC.
In this study, we identified 224 differentially expressed TM-related genes for the first time. Functional enrichment and pathway analyses revealed that these genes were highly involved in telomere-associated pathways, including cell proliferation and cellular senescence. Protein-protein interaction (PPI) analysis identified eight hub TM-related genes (RNASEH2A, KPNA2, AURKB, FOXM1, MKI67, RAD54L, PLK1, and KIF4A), all of which were positively correlated with telomere maintenance. Furthermore, a novel TM-related prognostic signature comprising seven genes (KPNA2, CACNA1B, IRAK1, CDCA8, RGMA, ETS2, and GNE) was developed using the LASSO Cox model. Notably, KPNA2 was identified as both a TM-related hub gene and a component of the prognostic signature. KPNA2 was found to be significantly upregulated in HCC and associated with poor clinical outcomes. Functional assays revealed that KPNA2 knockdown suppressed telomerase activity, inhibited tumor cell proliferation and metastasis, whereas its overexpression produced the opposite effects. Telomerase inhibition partially alleviated the inhibitory effect of KPNA2 overexpression on cell proliferation and migration.
This study identified eight TM-related hub genes with prognostic significance in HCC and established a novel TM-related gene signature. Furthermore, we validated KPNA2 as a key regulator of telomere maintenance and tumor progression in HCC, suggesting it as a potential therapeutic target for improving clinical management of HCC.
端粒维持机制（TMMs）在肝细胞癌（HCC）的发生和发展中发挥着独特作用。然而，HCC中端粒维持（TM）相关基因的预后相关性仍不清楚。
我们整合了来自公共数据库的TM相关基因的表达谱和相应的临床病理数据。进行单变量分析以鉴定预后基因，并使用Cytoscape软件验证TM相关网络中的枢纽基因。然后使用LASSO Cox回归算法构建了一种新的预后特征。最后，进行体外实验以探讨关键枢纽基因KPNA2在HCC端粒维持、肿瘤生长和转移中的功能作用。
在本研究中，我们首次鉴定出224个差异表达的TM相关基因。功能富集和通路分析表明，这些基因高度参与端粒相关通路，包括细胞增殖和细胞衰老。蛋白质-蛋白质相互作用（PPI）分析确定了8个枢纽TM相关基因（RNASEH2A、KPNA2、AURKB、FOXM1、MKI67、RAD54L、PLK1和KIF4A），所有这些基因均与端粒维持呈正相关。此外，使用LASSO Cox模型开发了一种包含7个基因（KPNA2、CACNA1B、IRAK1、CDCA8、RGMA、ETS2和GNE）的新的TM相关预后特征。值得注意的是，KPNA2被鉴定为既是TM相关枢纽基因又是预后特征的一个组成部分。发现KPNA2在HCC中显著上调，并与不良临床结果相关。功能测定表明，敲低KPNA2可抑制端粒酶活性，抑制肿瘤细胞增殖和转移，而其过表达则产生相反的效果。端粒酶抑制部分减轻了KPNA2过表达对细胞增殖和迁移的抑制作用。
本研究鉴定出8个在HCC中具有预后意义的TM相关枢纽基因，并建立了一种新的TM相关基因特征。此外，我们验证了KPNA2是HCC中端粒维持和肿瘤进展的关键调节因子，表明它是改善HCC临床管理的潜在治疗靶点。
