Transcriptomic profiling reveals mechanism, therapeutic potential, and prognostic value of cancer stemness characteristic in nasopharyngeal carcinoma

IF 3.9 4区 生物学 Q1 GENETICS & HEREDITY
Jin-Wei Chen, Run-Nan Shen, Jiang-Quan Zhu, Ying-Hang Wang, Liang-Min Fu, Yu-Hang Chen, Jia-Zheng Cao, Jin-Huan Wei, Jun-Hang Luo, Jia-Ying Li, Cheng-Peng Gui
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引用次数: 0

Abstract

Nasopharyngeal carcinoma (NPC) recurrence, distant metastasis, and drug resistance remain significant obstacles in clinical prognosis. Cancer stemness is hypothesized to be a key contributor, though direct evidence is sparse. We utilized bioinformatics and machine learning techniques on single-cell RNA-seq and bulk transcriptomic datasets, complemented by basic experiments, to investigate stemness-based characteristics in NPC. Our analysis identified two potential developmental trajectories of nasopharyngeal cancer cells, each exhibiting varying levels of stemness. We subsequently identified and validated a cancer stemness-related signature (STEM-signature). Single-cell profiling revealed enrichment of LAYN + CD8 + , CTLA4 + CD4 + , CXCL13 + CD4 + T cells, tumor-associated macrophages, and CD14 + monocytes in NPC patients with high stemness. NicheNet analysis suggested these immune cells regulate cancer stemness. Bulk transcriptomic analysis corroborated these findings, indicating a poor therapeutic response in high-stemness NPC. We predicted 13 potential drugs and identified 13 stemness-related miRNAs for NPC with high stemness. A Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model, based on this miRNA signature, predicted overall survival with an AUC of 0.71 and 0.72 in validation and testing sets, respectively. The miRNA-based stemness signature outperformed previous established signatures. Multivariate Cox regression analysis indicated that our prognostic signature could serve as an independent prognostic factor (p < 0.001). Basic experiments showed that miR-300, miR-361-5p, miR-1246, and miR-1290 enhanced the stemness characteristics of NPC cells, promoting proliferation, invasion, and migration. These findings suggest that these four stemness-related miRNAs could serve as therapeutic targets, potentially improving therapeutic responses by targeting stemness-related genes.

转录组学分析揭示鼻咽癌干性特征的机制、治疗潜力和预后价值
鼻咽癌复发、远处转移及耐药是影响鼻咽癌临床预后的重要障碍。尽管直接证据很少,但癌症干细胞被认为是一个关键因素。我们利用生物信息学和机器学习技术对单细胞RNA-seq和大量转录组数据集进行分析,并辅以基础实验,研究鼻咽癌的干细胞特征。我们的分析确定了鼻咽癌细胞的两种潜在的发育轨迹,每一种都表现出不同水平的干细胞。随后,我们确定并验证了一个癌症干细胞相关特征(STEM-signature)。单细胞分析显示,在高干性鼻咽癌患者中,LAYN + CD8 +、CTLA4 + CD4 +、CXCL13 + CD4 + T细胞、肿瘤相关巨噬细胞和CD14 +单核细胞富集。NicheNet分析表明,这些免疫细胞调节癌症的发生。大量转录组学分析证实了这些发现,表明高干性鼻咽癌的治疗反应较差。我们预测了13种潜在的药物,并鉴定了13种与高干性鼻咽癌相关的mirna。基于该miRNA特征的最小绝对收缩和选择算子(LASSO) Cox回归模型,在验证集和测试集中预测总生存期的AUC分别为0.71和0.72。基于mirna的干性签名优于先前建立的签名。多因素Cox回归分析表明,我们的预后特征可以作为一个独立的预后因素(p < 0.001)。基础实验表明,miR-300、miR-361-5p、miR-1246和miR-1290增强了鼻咽癌细胞的干性特征,促进了细胞的增殖、侵袭和迁移。这些发现表明,这四种与干细胞相关的mirna可以作为治疗靶点,通过靶向干细胞相关基因来改善治疗反应。
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来源期刊
CiteScore
3.50
自引率
3.40%
发文量
92
审稿时长
2 months
期刊介绍: Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?
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