与同源重组缺陷相关的长链非编码RNA特征在肝细胞癌肿瘤微环境与临床预后分析中的应用

A disulfidptosis-related lncRNA signature for analyzing tumor microenvironment and clinical prognosis in hepatocellular carcinoma

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Frontiers in Immunology

影响因子:5.9

分区:医学2区 / 免疫学2区

发表日期:2024

作者: Haishui Zheng, Jigan Cheng, Ziyun Zhuang, Duguang Li, Jing Yang, Fan Yuan, Xiaoxiao Fan, Xiaolong Liu

DOI: 10.3389/fimmu.2024.1412277

摘要

Disulfidptosis是一种新近发现的非凋亡性程序性细胞死亡形式，区别于传统的细胞死亡途径。然而，disulfidptosis相关的长链非编码RNA（DRLs）在肝细胞癌（HCC）中的预后意义及其作用机制尚未被充分研究。本研究利用TCGA数据库中HCC患者的RNA测序数据和临床信息，通过表达相关性和预后相关性分析，筛选出一组表现优异的长链非编码RNA。随后，采用Lasso回归分析建立了一个5-DRLs预后预测签名。该签名有效地区分了高风险和低风险患者，显示出明显的生存差异。多因素Cox回归分析证实，基于该签名的风险评分可以独立预测HCC患者的预后。进一步分析发现，两组患者在免疫细胞浸润和肿瘤突变负荷（TMB）方面存在显著差异，提示免疫机制与disulfidptosis可能存在关联。该签名在HCC的化疗药物敏感性和免疫治疗效果预测中也表现出潜在价值。最后，通过细胞和患者水平的实验验证，成功诱导出HCC细胞的disulfidptosis表型。总体而言，这一多层次方法揭示了DRLs在HCC中的表达特征，建立了具有预后和治疗指导意义的风险模型，为HCC的个体化治疗提供新思路。

Abstract

Disulfidptosis is a recently identified form of non-apoptotic programmed cell death which distinguishes itself from classical cell death pathways. However, the prognostic implications of disulfidptosis-related long non-coding RNAs (DRLs) and their underlying mechanisms in hepatocellular carcinoma (HCC) remain largely unexplored.In this study, we leveraged RNA-sequencing data and clinical information of HCC patients from the TCGA database. Through expression correlation and prognostic correlation analyses, we identified a set of top-performing long non-coding RNAs. Subsequently, a 5-DRLs predictive signature was established by conducting a Lasso regression analysis.This signature effectively stratified patients into high- and low-risk groups, revealing notable differences in survival outcomes. Further validation through univariate and multivariate Cox regression analyses confirmed that the risk score derived from our signature independently predicted the prognosis of HCC patients. Moreover, we observed significant disparities in immune cell infiltration and tumor mutation burden (TMB) between the two risk groups, shedding light on the potential connection between immune-related mechanisms and disulfidptosis. Notably, the signature also exhibited predictive value in the context of chemotherapeutic drug sensitivity and immunotherapy efficacy for HCC patients. Finally, we performed experimental validation at both cellular and patient levels and successfully induced a disulfidptosis phenotype in HCC cells.In general, this multifaceted approach provides a comprehensive overview of DRLs profiles in HCC, culminating in the establishment of a novel risk signature that holds promise for predicting prognosis and therapy outcomes of HCC patients.