Fan Songsong, Tang Yuhong, Cao Jun, Peng Rui, Su Bingbing, Tu Daoyuan, Yu Weidi, Chen Chen, Wang Shunyi, Jin Shengjie, Jiang Guoqing, Zhang Chi, Bai Dousheng
Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225000, China.
Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225000, China.
Biochem Genet. 2025 Apr 17. doi: 10.1007/s10528-025-11098-z.
High levels of M2 macrophages often correlate with poor prognosis. Endoglin (ENG) is a potential target for anti-angiogenesis therapy in various cancers, but the link between M2 macrophages and metabolism-related genes (MRGs) in hepatocellular carcinoma (HCC) is unclear. We employed cibersort analysis to identify genes associated with M2 macrophages and metabolic reprogramming in HCC, utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. TCGA data were stratified basis on ENG expression levels, and the relationships between ENG and relevant genes were assessed alongside clinical features. Furthermore, we validated ENG expression in HCC tissues and its correlation with M2 macrophages via qRT-PCR, Western blotting (WB), and immunohistochemistry (IHC). Patients with high ENG expression presented superior overall survival (OS) and longer progression-free survival (PFS). Univariate and multivariate regression analyses identified ENG as an independent prognostic predictor. Moreover, GSEA, GO, and KEGG analyses suggested a correlation between ENG-related gene expression and immunity, particularly TAMs. Additionally, ENG was found to reshape the tumor microenvironment (TME) of HCC and influence the response to immunotherapy. Single-cell analysis revealed the differential expression and distribution of ENG in the TME. In vitro experiments demonstrated lower ENG expression in HCC tissues than in paracancerous tissues, with a concomitant correlation with M2 macrophages. ENG emerges as a novel predictive marker for HCC, could reshap the TME and impacts the response to immunotherapy and provides a fresh perspective for investigating combined immunotherapy targeting MRGs in HCC.
高水平的M2巨噬细胞通常与预后不良相关。内皮糖蛋白（ENG）是各种癌症抗血管生成治疗的潜在靶点，但肝细胞癌（HCC）中M2巨噬细胞与代谢相关基因（MRGs）之间的联系尚不清楚。我们利用来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的数据，采用Cibersort分析来鉴定与HCC中M2巨噬细胞和代谢重编程相关的基因。根据ENG表达水平对TCGA数据进行分层，并评估ENG与相关基因之间的关系以及临床特征。此外，我们通过qRT-PCR、蛋白质印迹法（WB）和免疫组织化学（IHC）验证了ENG在HCC组织中的表达及其与M2巨噬细胞的相关性。ENG高表达的患者总生存期（OS）更好，无进展生存期（PFS）更长。单因素和多因素回归分析确定ENG为独立的预后预测指标。此外，基因集富集分析（GSEA）、基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析表明ENG相关基因表达与免疫，特别是肿瘤相关巨噬细胞（TAMs）之间存在相关性。此外，发现ENG可重塑HCC的肿瘤微环境（TME）并影响免疫治疗反应。单细胞分析揭示了ENG在TME中的差异表达和分布。体外实验表明，HCC组织中ENG的表达低于癌旁组织，且与M2巨噬细胞呈相关性。ENG成为HCC的一种新型预测标志物，可重塑TME并影响免疫治疗反应，为研究针对HCC中MRGs的联合免疫治疗提供了新的视角。
