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全面分析组蛋白去乙酰化酶在肝肝细胞癌中的预后意义和生物学功能。

Comprehensive Analysis of the Prognostic Implications and Biological Function of HDACs in Liver Hepatocellular Carcinoma.

机构信息

Laboratory of Biochemistry and Molecular Biology Research, Department of Laboratory Medicine, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.

Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.

出版信息

Int J Med Sci. 2024 Oct 28;21(14):2807-2823. doi: 10.7150/ijms.97169. eCollection 2024.

Abstract

The prognostic significance and biological functions of the histone deacetylases (HDACs) gene family in liver hepatocellular carcinoma (LIHC) have not been fully investigated. Using Kaplan-Meier and Cox regression analysis, this study determined if HDAC genes were relevant for prognosis in LIHC. A regression model utilizing HDAC genes and the least absolute shrinkage and selection operator (LASSO) was created to foretell LIHC risk. A selective inhibitor of endogenous HDACs, CKD-581, was studied and to determine its effects on the development, invasion, migration, and proliferation of LIHC cell lines. Six HDACs were identified as correlating with the prognosis of LIHC. Overall survival (OS) was found to be shorter in individuals with higher risk scores when compared to those with lower risk scores, according to survival study. Natural killer cell infiltration was higher in individuals with lower risk ratings, which was mainly explained by the type II interferon (IFN) response. Limiting the activity of endogenous HDACs caused LIHC cell death by preventing their migration, invasion, and proliferation. studies confirmed that blocking HDAC expression inhibited tumor growth in mice. Further mechanistic studies showed that inhibition of HDACs expression elevates the protein levels of P21 and P27, and reduces those of cyclins A2, B1, D1 and E1. The risk score prognostic model based on HDAC genes could provide a valuable prognostic biomarker for LIHC. CKD-581 prohibits LIHC progression via inhibiting the cell cycle signaling pathway. CKD-581 holds promise as a therapeutic agent for the clinical management of LIHC.

摘要

组蛋白去乙酰化酶(HDAC)基因家族在肝细胞癌(LIHC)中的预后意义和生物学功能尚未得到充分研究。本研究通过Kaplan-Meier 和 Cox 回归分析,确定 HDAC 基因是否与 LIHC 的预后相关。利用 HDAC 基因和最小绝对收缩和选择算子(LASSO)创建了一个回归模型,以预测 LIHC 风险。研究了内源性 HDAC 的选择性抑制剂 CKD-581,以确定其对 LIHC 细胞系的发展、侵袭、迁移和增殖的影响。鉴定出 6 个 HDAC 与 LIHC 的预后相关。生存研究发现,与低风险评分的个体相比,高风险评分的个体的总生存期(OS)更短。较低风险评分的个体中自然杀伤细胞浸润更高,这主要是由 II 型干扰素(IFN)反应解释的。限制内源性 HDAC 的活性通过阻止 LIHC 细胞的迁移、侵袭和增殖导致其死亡。体内研究证实,阻断 HDAC 表达可抑制小鼠肿瘤生长。进一步的机制研究表明,抑制 HDACs 的表达可提高 P21 和 P27 的蛋白水平,并降低 cyclins A2、B1、D1 和 E1 的水平。基于 HDAC 基因的风险评分预后模型可为 LIHC 提供有价值的预后生物标志物。CKD-581 通过抑制细胞周期信号通路来阻止 LIHC 的进展。CKD-581 有望成为治疗 LIHC 的临床管理的治疗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7375/11539383/0eb43493f202/ijmsv21p2807g001.jpg

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