Zhai Xiangyu, Li Kecheng, Ding Hailing, Wu Yanmei, Zhang Xinlu, Zhang Hao, Zhou Huaxin, Liu Chongzhong, Zhang Zili, Jin Bin
Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, China.
Shandong Province Engineering Research Center for Multidisciplinary Research on Hepatobiliary and Pancreatic Malignant Tumors, Jinan, China.
Front Immunol. 2025 Jun 17;16:1602831. doi: 10.3389/fimmu.2025.1602831. eCollection 2025.
Anoikis is a distinct form of programmed cell death, differing from classical apoptosis, and its role in malignant tumor progression, particularly in hepatocellular carcinoma (HCC), remains insufficiently understood. This study aims to elucidate the prognostic significance and therapeutic relevance of anoikis-related genes (ARGs) in HCC.
We systematically analyzed the expression, mutation, and copy number variation profiles of 27 known ARGs in HCC using public datasets. Unsupervised consensus clustering was performed to classify patients into anoikis subtypes. Weighted Gene Co-expression Network Analysis (WGCNA) identified hub gene modules, and LASSO Cox regression was applied to construct a prognostic risk score model. Correlations between the risk model and clinical outcomes, tumor microenvironment (TME) characteristics, and immunotherapy responses were evaluated. Single-cell RNA-seq and pan-cancer analyses were conducted to explore gene expression across cell types and cancer types. Finally, in vitro experiments were performed to validate the biological function of model genes.
Two distinct anoikis subtypes with differing prognoses and TME features were identified in HCC. A two-gene prognostic model (TTC26 and TPX2) was developed, demonstrating robust performance in predicting patient outcomes. High-risk patients exhibited lower overall survival and distinct immune infiltration profiles. Pan-cancer analysis showed widespread dysregulation of TTC26 and TPX2. In vitro experiments confirmed that TTC26 promotes HCC cell proliferation, migration, and invasion.
Our findings reveal that anoikis-related molecular classification is closely linked to HCC prognosis and immune landscape. The established prognostic model has potential clinical utility for risk stratification and treatment guidance. TTC26 may serve as a novel biomarker and therapeutic target in HCC.
失巢凋亡是一种独特的程序性细胞死亡形式，不同于经典的细胞凋亡，其在恶性肿瘤进展中的作用，尤其是在肝细胞癌（HCC）中的作用，仍未得到充分了解。本研究旨在阐明失巢凋亡相关基因（ARGs）在HCC中的预后意义和治疗相关性。
我们使用公共数据集系统分析了HCC中27个已知ARGs的表达、突变和拷贝数变异谱。进行无监督一致性聚类以将患者分类为失巢凋亡亚型。加权基因共表达网络分析（WGCNA）确定了枢纽基因模块，并应用LASSO Cox回归构建预后风险评分模型。评估了风险模型与临床结局、肿瘤微环境（TME）特征和免疫治疗反应之间的相关性。进行单细胞RNA测序和泛癌分析以探索不同细胞类型和癌症类型中的基因表达。最后，进行体外实验以验证模型基因的生物学功能。
在HCC中鉴定出两种具有不同预后和TME特征的独特失巢凋亡亚型。开发了一个双基因预后模型（TTC26和TPX2），在预测患者结局方面表现出强大的性能。高危患者的总生存期较低，且具有独特的免疫浸润谱。泛癌分析显示TTC26和TPX2广泛失调。体外实验证实TTC26促进HCC细胞增殖、迁移和侵袭。
我们的研究结果表明，失巢凋亡相关的分子分类与HCC预后和免疫格局密切相关。所建立的预后模型在风险分层和治疗指导方面具有潜在的临床应用价值。TTC26可能作为HCC的一种新型生物标志物和治疗靶点。
