肿瘤细胞治疗研究
英文原题：Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma.
结果：生存分析显示，高表达组与低表达组的总生存期存在显著差异（p = 0.0092），高表达组的 COAD 患者 5 年生存率更差。
背景：Delta样配体3（DLL3）是NOTCH配体家族成员之一，在某些癌症中具有促癌或抑癌作用，但DLL3在结肠腺癌（COAD）中的作用尚未得到深入研究。材料与方法：首先，利用癌症基因组图谱（TCGA）数据集的Kaplan–Meier（K-M）曲线评估DLL3对COAD预后的影响，并在临床样本中通过免疫组化进一步验证。随后分析基因表达综合数据库（GEO）及TCGA的COAD样本数据，筛选DLL3相关差异表达基因（DEG）。采用基因本体（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）探索DLL3相关基因影响COAD发生和预后的潜在机制。基于DLL3相关特征基因构建预后模型和列线图。最后采用CIBERSORT评估COAD样本中免疫细胞类型比例。结果：生存分析显示，高、低DLL3表达组总生存期存在显著差异（p=0.0092），高表达患者5年生存率较低。基因功能富集分析显示，DLL3相关DEG主要富集于肿瘤和免疫相关信号通路，包括AMPK通路和动物线粒体自噬。GSEA比较COAD肿瘤与正常组织及DLL3高、低表达组发现，AMPK信号通路和动物线粒体自噬受到抑制。基于DLL3相关特征基因构建的列线图具有较好的预后预测效果。DLL3与间质树突状细胞（iDC）、NK细胞和间质树突状Tem细胞的相关性最高。DLL3也具有COAD诊断价值。临床样本中，结肠癌组织DLL3表达高于邻近对照组织（p<0.0001），转移灶高于原发灶（p=0.0056）；DLL3表达与分期相关，高表达可预测较差总生存期（p=0.004）。结论：DLL3可能具有预后价值和个体化治疗潜力，也可能用于COAD诊断。
Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth. Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample. Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group ( p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control ( p < 0.0001) and in metastasis than in primary lesion ( p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival ( p = 0.004). Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.
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