Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming City, Yunnan Province, 650101, China.
Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, NO.374 Dianmian Road, Kunming City, Yunnan Province, 650101, China.
Biochem Biophys Res Commun. 2024 Dec 20;739:150576. doi: 10.1016/j.bbrc.2024.150576. Epub 2024 Aug 21.
Cellular senescence, an emerging hallmark of cancer, has garnered increasing attention in recent years. However, its role in hepatocellular carcinoma (HCC) is still not well understood. Furthermore, there is a lack of comprehensive biomarkers to predict prognosis and assess senescence and immune characteristics in HCC patients. To address these gaps, we conducted functional studies on bleomycin-induced senescent Hepa1-6 cells and developed the Cellular Senescence Score (CSS) based on four core cellular senescence-related genes. We found that the cellular senescence signaling pathway was enriched among the risk genes associated with unfavorable prognosis in HCC patients. The senescence associated secretory phenotype (SASP) derived from senescent Hepa1-6 cells induced an increase in CD3 CD8 CD279 T cells. The senescent Huh7 cells expressed higher levels of pro-angiogenic genes compared to their immortal counterparts. The CSS was constructed on the basis of BMI1, EZH2, NPM1, and ME1. HCC Patients in the high-CSS group had significantly shorter overall survival compared to those in the low-CSS group. In contrast to the low-CSS group, the high-CSS group exhibited more senescence characteristics at both the overall tumor microenvironment and single-cell levels. Three distinct senescence patterns were identified in hepatoma cells: oxidative stress related senescence, metabolism related senescence, and immune related senescence. The high-CSS group showed elevated TP53 mutation rate, diminished immune cell infiltration, and enhanced expression levels of immune checkpoint molecules compared to the low-CSS group. Moreover, the high-CSS group displayed a greater proportion of patients responsive to immune checkpoint therapy compared to the low-CSS group. In summary, the impacts of cellular senescence on HCC are multifaceted, and the tumor-promoting effects may be caused by SASP remodeling the HCC microenvironment rather than by the senescent hepatoma cells themselves. The CSS is a promising biomarker capable of predicting prognosis and assessing senescence and immune characteristics in HCC.
细胞衰老作为癌症的一个新兴标志，近年来受到了越来越多的关注。然而，它在肝细胞癌（HCC）中的作用仍未被充分理解。此外，目前缺乏全面的生物标志物来预测 HCC 患者的预后，并评估其衰老和免疫特征。为了解决这些问题，我们对博来霉素诱导的衰老 Hepa1-6 细胞进行了功能研究，并基于四个核心细胞衰老相关基因开发了细胞衰老评分（CSS）。我们发现，细胞衰老信号通路在与 HCC 患者不良预后相关的风险基因中富集。来自衰老 Hepa1-6 细胞的衰老相关分泌表型（SASP）可诱导 CD3+CD8+CD279+T 细胞增加。与永生化对照相比，衰老的 Huh7 细胞表达了更高水平的促血管生成基因。CSS 是基于 BMI1、EZH2、NPM1 和 ME1 构建的。CSS 高分组 HCC 患者的总生存期明显短于 CSS 低分组。与 CSS 低分组相比，CSS 高分组在整体肿瘤微环境和单细胞水平上均表现出更多的衰老特征。在肝癌细胞中鉴定出三种不同的衰老模式：氧化应激相关衰老、代谢相关衰老和免疫相关衰老。与 CSS 低分组相比，CSS 高分组显示出更高的 TP53 突变率、免疫细胞浸润减少和免疫检查点分子表达增强。此外，CSS 高分组中对免疫检查点治疗有反应的患者比例高于 CSS 低分组。综上所述，细胞衰老对 HCC 的影响是多方面的，其促进肿瘤的作用可能是由 SASP 重塑 HCC 微环境引起的，而不是由衰老的肝癌细胞本身引起的。CSS 是一种有前途的生物标志物，能够预测 HCC 的预后，并评估其衰老和免疫特征。
