通过深度转录组学分析阐明动态肿瘤微环境和肝癌中MRE11表达模式的治疗意义。

IF 6 2区 医学 Q1 ONCOLOGY
Ruiqiu Chen, Chaohui Xiao, Zizheng Wang, Guineng Zeng, Shaoming Song, Gong Zhang, Lin Zhu, Penghui Yang, Rong Liu
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引用次数: 0

摘要

目的:本研究旨在通过深入的转录组学分析,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MRE11进一步验证其免疫调节和预后意义。方法:我们采用基于汇总数据的孟德尔随机化(SMR)分析来鉴定与HCC有因果关系的基因,并将这些基因与DNA损伤修复(DDR)基因交叉,从而鉴定出MRE11。通过转录组学数据分析,对肝癌中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,通过qPCR、免疫组织化学和Western blotting验证了MRE11在HCC组织中的表达差异。利用公开的单细胞RNA测序(scRNA-seq)数据和空间转录组学来探索MRE11在原发性和免疫治疗后肿瘤微环境(TME)中的动态机制。我们还筛选了差异表达基因,并使用101机器学习算法构建了稳健的HCC预后模型。结果:我们的研究结果表明,MRE11的高表达与HCC的不良预后密切相关。在原发TME中,MRE11调节免疫应答,促进免疫逃避。单细胞分析显示,MRE11高表达组的肿瘤具有显著的异质性,特别是在巨噬细胞和恶性细胞中,MRE11通过cGAS-STING途径和HGF-MET轴调节免疫逃避和肿瘤进展。在免疫治疗下,MRE11的高表达促进了上皮-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,我们的预测模型在多个数据集上显示出很强的预测准确性。结论:MRE11高表达在肝癌细胞免疫微环境调控、免疫逃避和肿瘤进展中起重要作用。MRE11成为HCC诊断的一个有前景的生物标志物和个性化免疫治疗的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Elucidating the dynamic tumor microenvironment through deep transcriptomic analysis and therapeutic implication of MRE11 expression patterns in hepatocellular carcinoma.

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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