Chen Zi-An, Tian Hui, Yao Dong-Mei, Zhang Yuan, Feng Zhi-Jie, Yang Chuan-Jie
Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Front Oncol. 2021 Sep 9;11:738477. doi: 10.3389/fonc.2021.738477. eCollection 2021.
Ferroptosis is a novel form of regulated cell death involved in tumor progression. The role of ferroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains unclear.
RNA-seq and clinical data for HCC patients were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) portal. Bioinformatics methods, including weighted gene coexpression network analysis (WGCNA), Cox regression, and least absolute shrinkage and selection operator (LASSO) analysis, were used to identify signature markers for diagnosis/prognosis. The tumor microenvironment, immune infiltration and functional enrichment were compared between the low-risk and high-risk groups. Subsequently, small molecule drugs targeting ferroptosis-related signature components were predicted the L1000FWD and PubChem databases.
The prognostic model consisted of 2 ferroptosis-related mRNAs (SLC1A5 and SLC7A11) and 8 ferroptosis-related lncRNAs (AC245297.3, MYLK-AS1, NRAV, SREBF2-AS1, AL031985.3, ZFPM2-AS1, AC015908.3, MSC-AS1). The areas under the curves (AUCs) were 0.830 and 0.806 in the training and test groups, respectively. Decision curve analysis (DCA) revealed that the ferroptosis-related signature performed better than all pathological characteristics. Multivariate Cox regression analysis showed that the risk score was an independent prognostic factor. The survival probability of low- and high-risk patients could be clearly distinguished by the principal component analysis (PCA) plot. The risk score divided HCC patients into two distinct groups in terms of immune status, especially checkpoint gene expression, which was further supported by the Gene Ontology (GO) biological process, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, several small molecule drugs (SIB-1893, geldanamycin and PD-184352, etc) targeting ferroptosis-related signature components were identified for future reference.
We constructed a new ferroptosis-related mRNA/lncRNA signature for HCC patients. The model can be used for prognostic prediction and immune evaluation, providing a reference for immunotherapies and targeted therapies.
铁死亡是一种参与肿瘤进展的新型程序性细胞死亡形式。铁死亡相关长链非编码RNA（lncRNA）在肝细胞癌（HCC）中的作用尚不清楚。
从癌症基因组图谱（TCGA）基因组数据共享库（GDC）门户下载HCC患者的RNA测序和临床数据。采用包括加权基因共表达网络分析（WGCNA）、Cox回归和最小绝对收缩与选择算子（LASSO）分析在内的生物信息学方法来识别诊断/预后的特征标志物。比较低风险和高风险组之间的肿瘤微环境、免疫浸润和功能富集情况。随后，在L1000FWD和PubChem数据库中预测靶向铁死亡相关特征成分的小分子药物。
预后模型由2个铁死亡相关的mRNA（溶质载体家族1成员5（SLC1A5）和溶质载体家族7成员11（SLC7A11））和8个铁死亡相关的lncRNA（AC245297.3、肌球蛋白轻链激酶反义RNA1（MYLK-AS1）、核受体辅助激活因子相关RNA（NRAV）、固醇调节元件结合转录因子2反义RNA1（SREBF2-AS1）、AL031985.3、锌指蛋白M2反义RNA1（ZFPM2-AS1）、AC015908.3、间充质干细胞反义RNA1（MSC-AS1））组成。训练组和测试组的曲线下面积（AUC）分别为0.830和0.806。决策曲线分析（DCA）显示，铁死亡相关特征比所有病理特征表现更好。多变量Cox回归分析表明，风险评分是一个独立的预后因素。通过主成分分析（PCA）图可以清楚地区分低风险和高风险患者的生存概率。风险评分根据免疫状态，特别是检查点基因表达，将HCC患者分为两个不同的组，基因本体论（GO）生物学过程和京都基因与基因组百科全书（KEGG）分析进一步支持了这一点。最后，确定了几种靶向铁死亡相关特征成分的小分子药物（SIB-1893、格尔德霉素和PD-184352等）以供未来参考。
我们为HCC患者构建了一种新的铁死亡相关mRNA/lncRNA特征。该模型可用于预后预测和免疫评估，为免疫治疗和靶向治疗提供参考。
