Liang Jun, Chen Di, Liang Huiyu
Department of General Practice, Shanghai Pudong New Area Nanmatou Community Health Service Center, Shanghai, 200125, China.
Department of Infectious Diseases, Xinjiang Uygur Autonomous Region People's Hospital, Urumchi, 830000, China.
Discov Oncol. 2025 Jul 26;16(1):1411. doi: 10.1007/s12672-025-03201-y.
Hepatocellular carcinoma (HCC), a prevalent and highly lethal malignancy, is notorious for its aggressive nature and inherent tendency to metastasize, posing significant challenges in clinical management and prognosis. Hypoxia, a pivotal characteristic of the tumor microenvironment (TME) in hepatocellular HCC, is intimately linked to disease progression and unfavorable patient outcomes, underscoring its critical role in shaping the malignant behavior of this cancer.
Our research leveraged single-cell RNA sequencing technology to dissect the heterogeneity of the HCC TME, focusing on hypoxia-related genes. To probe the effects of hypoxia on HCC invasion, we developed the Cell Hypoxia-Related Prognostic Feature (CHPF). We analyzed transcriptome data from the The Cancer Genome Atlas (TCGA) database and the GSE149614 dataset, employing computational methods such as UMAP, Weighted correlation network analysis (WGCNA), and CellChat to identify hypoxia cells, characterize cell subsets, and elucidate intercellular communications.
Our analysis revealed significant heterogeneity in hypoxia cell populations within the HCC TME, with distinct expression patterns of hypoxia-related genes in neoplastic and immune cells. Our analysis revealed distinct hypoxia subpopulations within HCC, with significant overexpression of genes like MEG3, KLF6 and JUN in hypoxia cells. We identified a unique hypoxia subpopulation with high invasive potential and constructed a prognostic model based on H2-specific transcription factors including LRP10、MED8、NOL10、NOP58 and REXO4. The model demonstrated significant predictive value for lifespan of patients as verified in the TCGA dataset and an external validation group.
Key transcription factors like NOP58, MED8 play pivotal roles in hypoxia-induced HCC invasion and metastasis, and a predictive model based on these factors forecasts HCC survival. Our findings provide novel molecular markers and therapeutic targets for HCC, highlighting the importance of considering the hypoxia TME in diagnostic and treatment strategies.
肝细胞癌（HCC）是一种常见且致死率高的恶性肿瘤，以其侵袭性和固有的转移倾向而闻名，给临床管理和预后带来了重大挑战。缺氧是肝细胞癌肿瘤微环境（TME）的一个关键特征，与疾病进展和患者不良预后密切相关，凸显了其在塑造这种癌症恶性行为中的关键作用。
我们的研究利用单细胞RNA测序技术剖析HCC TME的异质性，重点关注缺氧相关基因。为了探究缺氧对HCC侵袭的影响，我们开发了细胞缺氧相关预后特征（CHPF）。我们分析了来自癌症基因组图谱（TCGA）数据库和GSE149614数据集的转录组数据，采用诸如UMAP、加权相关网络分析（WGCNA）和CellChat等计算方法来识别缺氧细胞、表征细胞亚群并阐明细胞间通讯。
我们的分析揭示了HCC TME内缺氧细胞群体的显著异质性，肿瘤细胞和免疫细胞中缺氧相关基因具有不同的表达模式。我们的分析揭示了HCC内不同的缺氧亚群，缺氧细胞中MEG3、KLF6和JUN等基因显著过表达。我们鉴定出一个具有高侵袭潜力的独特缺氧亚群，并基于包括LRP10、MED8、NOL10、NOP58和REXO4在内的H2特异性转录因子构建了一个预后模型。该模型在TCGA数据集和一个外部验证组中得到验证，对患者寿命具有显著的预测价值。
NOP58、MED8等关键转录因子在缺氧诱导的HCC侵袭和转移中起关键作用，基于这些因子的预测模型可预测HCC患者的生存期。我们的研究结果为HCC提供了新的分子标志物和治疗靶点，突出了在诊断和治疗策略中考虑缺氧TME的重要性。
