基于单细胞转录组学探究LNPEP在胆管癌顺铂耐药中的作用

Investigating the Role of LNPEP in Cisplatin Resistance in Cholangiocarcinoma Based on Single-Cell Transcriptomics

摘要: 背景：胆管癌(CCA)是一种恶性肿瘤，顺铂等化疗药物的耐药性显著影响治疗效果，其机制尚未完全阐明。本研究旨在通过分析TCGA-CHOL数据集和单细胞RNA测序数据，揭示铂类耐药相关的分子特征，重点探索LNPEP (Leucyl and Cystinyl Aminopeptidase)在胆管癌铂类耐药中的潜在作用，并探讨其在耐药表型形成和肿瘤微环境调控中的作用。方法：基于TCGA-CHOL转录组数据，进行差异表达分析，筛选出铂类耐药相关的差异表达基因(PR-DEGs)。然后，通过Cox比例风险回归和LASSO回归构建铂类耐药相关的预后模型。随后，结合单细胞RNA测序数据，分析LNPEP在不同细胞亚群中的表达特征，并通过细胞通讯分析揭示LNPEP在耐药亚群中的潜在作用机制。结果：通过联合分析TCGA-CHOL转录组数据和单细胞RNA测序数据，我们发现LNPEP是胆管癌铂类耐药的关键基因，并在单细胞数据中筛选出相关的耐药亚群(CCA-R)。该亚群与肿瘤微环境中的成纤维细胞、巨噬细胞和内皮细胞之间存在显著的细胞间通讯。进一步的NicheNet分析表明，LNPEP可能通过ECM重塑、炎症因子和生长因子相关信号通路维持耐药表型。结论：本研究系统解析了胆管癌铂类耐药的分子特征，发现LNPEP在耐药表型的形成中可能发挥关键作用。通过单细胞异质性与肿瘤微环境的互作分析，本研究为胆管癌铂类耐药的机制研究提供了新的视角，并为精准治疗和耐药预测提供了新的分子标志物。LNPEP可能成为胆管癌铂类耐药的新靶点，为未来的联合干预治疗提供理论基础。

Abstract: Background: Cholangiocarcinoma (CCA) is a malignant tumor, and the resistance to chemotherapy drugs such as cisplatin significantly affects treatment outcomes. The mechanism of this resistance is not fully understood. This study aims to reveal the molecular characteristics associated with platinum resistance by analyzing the TCGA-CHOL dataset and single-cell RNA sequencing data, focusing on exploring the potential role of LNPEP (Leucyl and Cystinyl Aminopeptidase) in cisplatin resistance in CCA, and investigating its role in the formation of resistance phenotypes and regulation of the tumor microenvironment. Methods: Differential expression analysis was conducted based on the TCGA-CHOL transcriptomic data to identify platinum resistance-related differentially expressed genes (PR-DEGs). Subsequently, Cox proportional hazards regression and LASSO regression were applied to construct a platinum resistance-related prognostic model. Single-cell RNA sequencing data were then combined to analyze the expression characteristics of LNPEP in different cell subpopulations, and cell communication analysis was performed to uncover the potential mechanisms of LNPEP in resistance subpopulations. Results: By integrating the TCGA-CHOL transcriptomic data and single-cell RNA sequencing data, we identified LNPEP as a key gene involved in cisplatin resistance in CCA. We also identified related resistance subpopulations (CCA-R) in single-cell data, which exhibited significant cell-to-cell communication with fibroblasts, macrophages, and endothelial cells in the tumor microenvironment. Further NicheNet analysis suggested that LNPEP may maintain the resistance phenotype through ECM remodeling, inflammatory factors, and growth factor-related signaling pathways. Conclusion: This study systematically analyzes the molecular characteristics of platinum resistance in CCA and reveals that LNPEP may play a crucial role in the formation of the resistance phenotype. By analyzing the single-cell heterogeneity and tumor microenvironment interactions, this study provides new insights into the mechanisms of platinum resistance in CCA and identifies new molecular biomarkers for precision treatment and resistance prediction. LNPEP may become a novel target for platinum resistance in CCA and provide a theoretical basis for future combination therapies.