Dalian Medical University, Dalian, 116000, China.
Clinical Medical College, Yangzhou University, Yangzhou, 225000, China.
J Cancer Res Clin Oncol. 2024 Apr 1;150(4):171. doi: 10.1007/s00432-024-05665-x.
Tryptophan (Trp) is an essential amino acid. Increasing evidence suggests that tryptophan metabolism plays a complex role in immune escape from Lung adenocarcinoma (LUAD). However, the role of long non-coding RNAs (lncRNAs) in tryptophan metabolism remains to be investigated.
This study uses The Cancer Genome Atlas (TCGA)-LUAD dataset as the training cohort, and several datasets from the Gene Expression Omnibus (GEO) database are merged into the validation cohort. Genes related to tryptophan metabolism were identified from the Molecular Signatures Database (MSigDB) database and further screened for lncRNAs with Trp-related expression. Subsequently, a prognostic signature of lncRNAs related to tryptophan metabolism was constructed using Cox regression analysis, (Least absolute shrinkage and selection operator regression) and LASSO analysis. The predictive performance of this risk score was validated by Kaplan-Meier (KM) survival analysis, (receiver operating characteristic) ROC curves, and nomograms. We also explored the differences in immune cell infiltration, immune cell function, tumor mutational load (TMB), tumor immune dysfunction and exclusion (TIDE), and anticancer drug sensitivity between high- and low-risk groups. Finally, we used real-time fluorescence quantitative PCR, CCK-8, colony formation, wound healing, transwell, flow cytometry, and nude mouse xenotransplantation models to elucidate the role of ZNF8-ERVK3-1 in LUAD.
We constructed 16 tryptophan metabolism-associated lncRNA prognostic models in LUAD patients. The risk score could be used as an independent prognostic indicator for the prognosis of LUAD patients. Kaplan-Meier survival analysis, ROC curves, and risk maps validated the prognostic value of the risk score. The high-risk and low-risk groups showed significant differences in phenotypes, such as the percentage of immune cell infiltration, immune cell function, gene mutation frequency, and anticancer drug sensitivity. In addition, patients with high-risk scores had higher TMB and TIDE scores compared to patients with low-risk scores. Finally, we found that ZNF8-ERVK3-1 was highly expressed in LUAD tissues and cell lines. A series of in vitro experiments showed that knockdown of ZNF8-ERVK3-1 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. In vivo experiments with xenografts have shown that knocking down ZNF8-ERVK3-1 can significantly inhibit tumor size and tumor proliferation.
We constructed a new prognostic model for tryptophan metabolism-related lncRNA. The risk score was closely associated with common clinical features such as immune cell infiltration, immune-related function, TMB, and anticancer drug sensitivity. Knockdown of ZNF8-ERVK3-1 inhibited LUAD cell proliferation, migration, invasion, and G0/G1 phase blockade and promoted apoptosis.
色氨酸（Trp）是一种必需氨基酸。越来越多的证据表明，色氨酸代谢在肺腺癌（LUAD）的免疫逃逸中发挥着复杂的作用。然而，长链非编码 RNA（lncRNA）在色氨酸代谢中的作用仍有待研究。
本研究使用癌症基因组图谱（TCGA）-LUAD 数据集作为训练队列，并合并了来自基因表达综合数据库（GEO）的多个数据集作为验证队列。从分子特征数据库（MSigDB）数据库中鉴定与色氨酸代谢相关的基因，并进一步筛选与 Trp 表达相关的 lncRNA。随后，使用 Cox 回归分析、（最小绝对收缩和选择算子回归）和 LASSO 分析构建与色氨酸代谢相关的 lncRNA 的预后特征。Kaplan-Meier（KM）生存分析、（受试者工作特征）ROC 曲线和列线图验证了该风险评分的预测性能。我们还探讨了高风险组和低风险组之间免疫细胞浸润、免疫细胞功能、肿瘤突变负荷（TMB）、肿瘤免疫功能障碍和排除（TIDE）以及抗癌药物敏感性的差异。最后，我们使用实时荧光定量 PCR、CCK-8、集落形成、划痕愈合、Transwell、流式细胞术和裸鼠异种移植模型来阐明 ZNF8-ERVK3-1 在 LUAD 中的作用。
我们构建了 16 个与 LUAD 患者色氨酸代谢相关的 lncRNA 预后模型。风险评分可作为 LUAD 患者预后的独立预后指标。Kaplan-Meier 生存分析、ROC 曲线和风险图验证了风险评分的预后价值。高风险组和低风险组在表型方面存在显著差异，如免疫细胞浸润百分比、免疫细胞功能、基因突变频率和抗癌药物敏感性。此外，与低风险组相比，高风险组患者的 TMB 和 TIDE 评分更高。最后，我们发现 ZNF8-ERVK3-1 在 LUAD 组织和细胞系中高表达。一系列体外实验表明，敲低 ZNF8-ERVK3-1 抑制细胞增殖、迁移和侵袭，导致细胞周期停滞在 G0/G1 期，并增加细胞凋亡。裸鼠异种移植实验表明，敲低 ZNF8-ERVK3-1 可显著抑制肿瘤大小和肿瘤增殖。
我们构建了一个新的与色氨酸代谢相关的 lncRNA 预后模型。风险评分与常见的临床特征密切相关，如免疫细胞浸润、免疫相关功能、TMB 和抗癌药物敏感性。敲低 ZNF8-ERVK3-1 抑制 LUAD 细胞增殖、迁移、侵袭和 G0/G1 期阻滞，并促进细胞凋亡。
