整合单细胞和空间转录组测序发现 CDKN2A 是内皮细胞中的衰老生物标志物,与肝癌恶性程度有关。

IF 2.7 3区 医学 Q3 ONCOLOGY
Yue Ma, Chenhe Yi, Ning Cai, Jinhong Chen
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引用次数: 0

摘要

目的:高度复杂的肿瘤微环境使肝细胞癌(HCC)成为全球恶性程度最高的肿瘤之一。细胞衰老在 HCC 中的作用已逐渐被认识。本研究旨在从单细胞和空间维度全面阐明HCC的衰老相关特征:方法:利用单细胞RNA测序(scRNA-Seq)数据阐明HCC多种细胞类型中衰老相关基因(SRGs)的异质性。空间转录组RNA测序(stRNA-Seq)数据用于描述SRGs的空间维度特征。利用 HCC 的批量测序(bulk-Seq)数据构建了基于 SRGs 的预后模型。分析了衰老内皮细胞(ECs)在肿瘤微环境中的细胞间相互作用。然后,通过体外和体内实验验证了衰老内皮细胞的作用:结果:HCC 肿瘤微环境中不同类型细胞的衰老程度表现出很大的异质性,其中 EC 表现出最突出的衰老表型。衰老的心血管细胞通过与其他细胞类型的交流激活了特定的调控通路,从而对肿瘤的进展产生了潜在的影响。空间分析表明,衰老的EC主要位于HCC的核心区域。衰老的EC与免疫细胞的相互作用暗示了它们在肿瘤进展和免疫治疗反应中的作用。此外,通过构建预后模型,CDKN2A 被确定为影响 HCC 预后的独立风险因素。高风险患者的预后更差。实验验证表明,由CDKN2A决定的衰老EC表现出分泌表型。此外,CDKN2A过表达的衰老EC会促进HCC的增殖和迁移:本研究认识到 CDKN2A 定义的衰老 ECs 在促进肿瘤进展中的关键作用,为研究 HCC 中 ECs 的衰老提供了新的思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integration of single-cell and spatial transcriptome sequencing identifies CDKN2A as a senescent biomarker in endothelial cells implicating hepatocellular carcinoma malignancy.

Purpose: Highly complex tumor microenvironment makes hepatocellular carcinoma (HCC) as one of the most malignant tumors worldwide. The role of cellular senescence in HCC has been gradually recognized. The present study aimed to comprehensively elucidate the senescence-related features of HCC in single-cell and spatial dimension.

Methods: Single-cell RNA sequencing (scRNA-Seq) data was used to clarify the heterogeneity of senescence-related genes (SRGs) among multiple cell types within HCC. Spatial transcriptome RNA sequencing (stRNA-Seq) data was used for depicting SRGs features in spatial dimension. A prognostic model based on SRGs was constructed by using of bulk sequencing (bulk-Seq) data of HCC. The cell-cell interaction of senescent endothelial cells (ECs) in tumor microenvironment was analyzed. Then, the role of senescent ECs was verified through in vitro and in vivo experiments.

Results: The level of senescence demonstrated substantial heterogeneity among different cell types within tumor microenvironment of HCC, where ECs exhibited the most prominent senescent phenotype. Senescent ECs activated specific regulatory pathways through communicating with other cell types, with a potential impact on tumor progression. Spatial analysis revealed senescent ECs mainly located in the core region of HCC. The interaction of senescent ECs and immune cells implicated their role in tumor progression and immunotherapeutic response. In addition, CDKN2A was identified as an independent risk factor for HCC prognosis by constructing a prognostic model. Patients with high risk displayed an even worse outcome. The experimental verification indicated senescence of ECs determined by CDKN2A exhibited a secretory phenotype. Furthermore, senescent ECs with CDKN2A overexpression promote the proliferation and migration of HCC.

Conclusion: The present study recognizes the critical effect of senescent ECs defined by CDKN2A in the promotion of tumor progression, which sheds new light on the investigation of ECs senescence in HCC.

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来源期刊
CiteScore
4.00
自引率
2.80%
发文量
577
审稿时长
2 months
期刊介绍: The "Journal of Cancer Research and Clinical Oncology" publishes significant and up-to-date articles within the fields of experimental and clinical oncology. The journal, which is chiefly devoted to Original papers, also includes Reviews as well as Editorials and Guest editorials on current, controversial topics. The section Letters to the editors provides a forum for a rapid exchange of comments and information concerning previously published papers and topics of current interest. Meeting reports provide current information on the latest results presented at important congresses. The following fields are covered: carcinogenesis - etiology, mechanisms; molecular biology; recent developments in tumor therapy; general diagnosis; laboratory diagnosis; diagnostic and experimental pathology; oncologic surgery; and epidemiology.
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