Senescent endothelial cells (ECs) in hepatocellular carcinoma (HCC) exhibit the most prominent senescent phenotype among various cell types within the tumor microenvironment.
Senescence-related genes (SRGs) show significant heterogeneity among different cell types in HCC.
Senescent ECs activate specific regulatory pathways through interactions with other cell types, potentially influencing tumor progression.
Spatial analysis indicates that senescent ECs are primarily located in the core region of HCC.
Interactions between senescent ECs and immune cells suggest their involvement in tumor progression and responses to immunotherapy.
CDKN2A is identified as an independent risk factor for poor prognosis in HCC, with higher risk associated with worse outcomes.
Senescent ECs defined by CDKN2A exhibit a secretory phenotype that promotes the proliferation and migration of HCC.
Simplified
PURPOSE: Highly complex tumor microenvironment makes hepatocellular carcinoma (HCC) as one of the most malignant tumors worldwide. The role of 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.
Key numbers
CDKN2A
Independent risk factor for prognosis
Identified as a key senescence-related gene in HCC.
217 patients
Patient cohort size
Used for constructing the senescence-related prognostic model.
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