Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Front Immunol. 2023 Jan 4;13:991604. doi: 10.3389/fimmu.2022.991604. eCollection 2022.
Cuproptosis was characterized as a novel type of programmed cell death. Recently, however, the role of cuproptosis-related long noncoding RNAs (CRLs) in tumors has not yet been studied. Identifying a predictive CRL signature in hepatocellular carcinoma (HCC) and investigating its putative molecular function were the goals of this work. Initially, Pearson's test was used to assess the relationship between lncRNAs and cuproptosis-associated genes obtained from HCC data of The Cancer Genome Atlas (TCGA). By implementing differential expression and univariate Cox analysis, 61 prognostic CRLs were subsequent to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. A prognostic risk score model was then constructed to evaluate its ability to predict patients' survival when combined with clinicopathological parameters in HCC. The five-lncRNA prognostic signature categorized the HCC patients into high- and low-risk groups. The low-risk group exhibited more sensitivity to elesclomol than the high-risk one. Surprisingly, distinct mitochondrial metabolism pathways connected to cuproptosis and pivotal immune-related pathways were observed between the two groups gene set enrichment analysis (GSEA). Meanwhile, there were substantial differences between the high-risk group and the low-risk group in terms of tumor-infiltrating immune cells (TIICs). Furthermore, a positive relationship was shown between the risk score and the expression of immune checkpoints. Additionally, differential expression of the five lncRNAs was confirmed in our own HCC samples and cell lines RT-qPCR. Finally, assays confirmed that WARS2-AS1 and MKLN1-AS knockdown could sensitize HCC cells to elesclomol-induced cuproptosis. Overall, our predictive signature may predict the prognosis of HCC patients in an independent manner, give a better understanding of how CRLs work in HCC, and offer therapeutic reference for patients with HCC.
铜死亡被定义为一种新型的程序性细胞死亡。然而，最近铜死亡相关的长链非编码 RNA（lncRNAs）在肿瘤中的作用尚未被研究。本研究旨在鉴定肝细胞癌（HCC）中的预测性 lncRNA 特征，并研究其潜在的分子功能。首先，使用 Pearson 检验评估了来自 TCGA HCC 数据的 lncRNAs 和铜死亡相关基因之间的关系。通过实施差异表达和单变量 Cox 分析，随后通过最小绝对收缩和选择算子（LASSO）Cox 回归分析，确定了 61 个预后 lncRNAs。然后构建了一个预后风险评分模型，以评估其与 HCC 的临床病理参数相结合预测患者生存的能力。该五-lncRNA 预后特征将 HCC 患者分为高风险和低风险组。低风险组对 elesclomol 的敏感性高于高风险组。令人惊讶的是，两组之间观察到与铜死亡和关键免疫相关途径相关的不同线粒体代谢途径的基因集富集分析（GSEA）。同时，高风险组和低风险组之间在肿瘤浸润免疫细胞（TIICs）方面存在显著差异。此外，风险评分与免疫检查点的表达之间存在正相关。此外，在我们自己的 HCC 样本和细胞系中通过 RT-qPCR 证实了这五个 lncRNAs 的差异表达。最后，细胞实验证实，WARS2-AS1 和 MKNL1-AS 的敲低可以使 HCC 细胞对 elesclomol 诱导的铜死亡敏感。总之，我们的预测特征可能独立地预测 HCC 患者的预后，更好地了解 lncRNAs 在 HCC 中的作用，并为 HCC 患者提供治疗参考。
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