Prediction of prognosis, immune infiltration, and personalized treatment of hepatocellular carcinoma by analysis of cuproptosis-related long noncoding RNAs and verification in vitro.
Prediction of prognosis, immune infiltration, and personalized treatment of hepatocellular carcinoma by analysis of cuproptosis-related long noncoding RNAs and verification in vitro.
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DOI：
10.3389/fonc.2023.1159126
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
肿瘤微环境(TME)、免疫治疗等与肝细胞癌(肝细胞癌)特征的关系尚不清楚。从癌症基因组图谱(TCGA)数据库中的374份肝细胞癌档案中鉴定出16个突触调节因子和356个突起相关的lncRNAs(CRLnc)。选择6个差异表达的CRLnc，构建基于CRLnc签名的预后风险模型(CRLncSig)。验证了该模型的预测能力。此外，基于6个lncRNAs和差异表达基因构建了一个Cuprotosis相关基因簇(CRGC)。通过不同的算法、肿瘤免疫功能障碍与排斥(TID)、肿瘤突变负荷(TMB)等方法，验证免疫细胞在TME、免疫治疗、CRLncSig和CRGC中的侵袭关系，并评估潜在药物和对这些药物的敏感性。选择LncRNA AL158166.1在肝癌组织和细胞系中进行验证，检测其在肝癌细胞中的下调和过表达的影响，并检测其铜浓度和脱落相关基因的表达。构建了具有良好预测能力的CRLncSig预后风险模型。与高危组相比，低风险组的总生存期(OS)更长，肿瘤纯度更低，免疫细胞浸润更广泛，免疫评分更高，免疫激活途径丰富，对免疫治疗的反应更积极。CRGC-B表现出最好的OS和最低的肿瘤分期，免疫细胞浸润分析与CRLncSig低危组相似。CRGC-B属于TME的“免疫高”组。低风险组的潮汐评分和对抗肿瘤药物的敏感性较高。LncRNA AL158166.1的风险比最高。AL158166.1在肝细胞癌组织中的表达水平高于正常肝组织。AL158166.1基因敲除可导致细胞内铜浓度升高，诱导DLAT低表达，抑制肝癌细胞的增殖和迁移，而AL158166.1过表达则相反。总体而言，我们构建并评估了一个新的CRLncSig预后风险模型和一个与脱垂相关的分子标记。模型和征象与肝细胞癌的预后、免疫侵袭和免疫治疗有关。抑制lncRNA AL158166.1可诱导细胞突起，显示出抑制肿瘤生长的潜力。检测CRLnc、CRLncSig和CRGC有助于提高对TME的认识，判断免疫治疗的有效性，并可作为判断肝细胞癌预后的指标。
The correlations between cuproptosis and long noncoding RNAs (lncRNAs) with the tumor microenvironment (TME), immunotherapy, and some other characteristics of hepatocellular carcinoma (HCC) remain unclear. Sixteen cuproptosis regulators and 356 cuproptosis-related lncRNAs (CRLnc) were identified from 374 HCC profiles in The Cancer Genome Atlas (TCGA) database. Six differentially expressed CRLnc were selected, and a prognostic risk model based on the CRLnc signature (CRLncSig) was constructed. The prognostic power of the model was verified. Moreover, a cuproptosis-related gene cluster (CRGC) was generated based on six lncRNAs and differentially expressed genes. The relationship between immune cell infiltration in the TME, immunotherapy, CRLncSig, and CRGC was demonstrated through various algorithms, Tumor Immune Dysfunction and Exclusion (TIDE), tumor mutational burden (TMB), etc. Potential drugs and sensitivity to those agents were evaluated for the risk model. LncRNA AL158166.1 was selected and verified in HCC tissues and cell lines, the impact of its knockdown and overexpression in HCC cells was examined, and the copper (Cu) concentration and the cuproptosis-related gene expression were detected. A CRLncSig prognostic risk model with good predictive ability was constructed. The low-risk group had a longer overall survival (OS), lower tumor purity, more extensive immune cell infiltration, higher immune score, enrichment in immune-activated pathways, and more positive response to immunotherapy versus the high-risk group. CRGC-B exhibited the best OS and the lowest tumor stage; the immune cell infiltration analysis was similar to the low-risk group in CRLncSig. CRGC-B belonged to the “immune-high” group of the TME. The low-risk group had a higher TIDE score and susceptibility to antitumor drugs. The lncRNA AL158166.1 had the highest hazard ratio. The levels of AL158166.1 were higher in HCC tissues versus healthy tissues. Knockdown of AL158166.1 could lead to an increase in intracellular Cu concentration, induce DLAT low expression, and inhibit the proliferation and migration of HCC cells, whereas overexpression of AL158166.1 exerted the reverse effect. Overall, a new CRLncSig prognostic risk model and a cuproptosis-related molecular signature were constructed and evaluated. The model and signature were associated with the prognosis, immune infiltration, and immunotherapy of HCC. Inhibiting the lncRNA AL158166.1 may induce cuproptosis and showed potential for the inhibition of tumors. Evaluation of the CRLnc, CRLncSig, and CRGC may enhance our understanding of the TME, determine the effectiveness of immunotherapy, and act as a marker for the prognosis of HCC.
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