Chen Ruiqiu, Xiao Chaohui, Wang Zizheng, Zeng Guineng, Song Shaoming, Zhang Gong, Zhu Lin, Yang Penghui, Liu Rong
The First School of Clinical Medicine, Lanzhou University, No. 1, Donggangxi Rd, Chengguan District, Lanzhou, 730000, Gansu, China.
Department of Hepato-Biliary-Pancreatic Surgery, the First Medical Centre, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.
Cancer Cell Int. 2025 Aug 21;25(1):311. doi: 10.1186/s12935-025-03931-7.
This study aims to explore the dynamic tumor microenvironment of hepatocellular carcinoma (HCC) through deep transcriptomic analysis and to identify key regulatory genes, among which MRE11 was further validated for its immunomodulatory and prognostic significance.
We performed Summary-data-based Mendelian Randomization (SMR) analysis to identify genes causally associated with HCC and intersected these with DNA damage repair (DDR) genes, leading to the identification of MRE11. A comprehensive evaluation of MRE11 expression in HCC was conducted using transcriptomic data analysis. We collected data from 92 HCC patient samples and validated MRE11 expression differences in HCC tissues through qPCR, immunohistochemistry, and Western blotting. Publicly available single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics were utilized to explore MRE11's dynamic mechanisms in the tumor microenvironment (TME) of both primary and post-immunotherapy cases. We also screened for differentially expressed genes and constructed a robust HCC prognosis model using 101 machine-learning algorithms.
Our results demonstrated that high MRE11 expression is strongly associated with poor prognosis in HCC. In the primary TME, MRE11 regulates immune responses, facilitating immune evasion. Single-cell analysis revealed significant tumor heterogeneity in MRE11 high-expression groups, particularly in macrophages and malignant cells, where MRE11 regulates immune evasion and tumor progression via the cGAS-STING pathway and HGF-MET axis. Under immunotherapy, high MRE11 expression facilitated epithelial-mesenchymal transition (EMT) and extensive remodeling of the TME. Furthermore, MRE11 dynamically enhanced macrophage regulation, exhibiting immunosuppressive and tumor-invasive features. Finally, our prognostic model exhibited strong predictive accuracy across multiple datasets.
High MRE11 expression is crucial in regulating the immune microenvironment in HCC, fostering immune evasion and driving tumor progression. MRE11 emerges as a promising biomarker for HCC diagnosis and a potential target for personalized immunotherapy.
本研究旨在通过深度转录组分析探索肝细胞癌（HCC）的动态肿瘤微环境，并鉴定关键调控基因，其中对MRE11的免疫调节和预后意义进行了进一步验证。
我们进行了基于汇总数据的孟德尔随机化（SMR）分析，以鉴定与HCC因果相关的基因，并将这些基因与DNA损伤修复（DDR）基因进行交叉分析，从而鉴定出MRE11。利用转录组数据分析对HCC中MRE11的表达进行了全面评估。我们收集了92例HCC患者样本的数据，并通过qPCR、免疫组织化学和蛋白质印迹法验证了HCC组织中MRE11的表达差异。利用公开可用的单细胞RNA测序（scRNA-seq）数据和空间转录组学技术，探索MRE11在原发性和免疫治疗后病例的肿瘤微环境（TME）中的动态机制。我们还筛选了差异表达基因，并使用101种机器学习算法构建了一个强大的HCC预后模型。
我们的结果表明，MRE11高表达与HCC预后不良密切相关。在原发性TME中，MRE11调节免疫反应，促进免疫逃逸。单细胞分析显示，MRE11高表达组存在显著的肿瘤异质性，尤其是在巨噬细胞和恶性细胞中，MRE11通过cGAS-STING途径和HGF-MET轴调节免疫逃逸和肿瘤进展。在免疫治疗下，MRE11高表达促进上皮-间质转化（EMT）和TME的广泛重塑。此外，MRE11动态增强巨噬细胞调节，表现出免疫抑制和肿瘤侵袭特征。最后，我们的预后模型在多个数据集中表现出强大的预测准确性。
MRE11高表达在调节HCC免疫微环境、促进免疫逃逸和驱动肿瘤进展方面至关重要。MRE11有望成为HCC诊断的生物标志物和个性化免疫治疗的潜在靶点。
