【摘要】 目的:利用单细胞转录组和孟德尔随机化，从多组学角度研究脂质代谢相关基因固醇载体蛋白2(SCP2)与前列腺癌(PCa)之间的关系。方法:从GSE120716、GSE157703和GSE141445数据集分别获得良恶性前列腺组织的单细胞转录组数据，对数据进行整合、质控和注释后将上皮细胞分为高SCP2表达组和低SCP2表达组，然后进一步进行差异分析和轨迹分析。随后从基因型-组织表达(GTEx)下载SCP2表达数量性状位点(eQTL)的单核苷酸多态性(SNP)数据，并从PCa协会调查癌症相关基因组改变小组(PRACTICAL)获得PCa结局数据进行孟德尔随机化分析，验证SCP2与PCa的因果关系。结果:高SCP2表达上皮细胞具有更旺盛的能量代谢以及增殖能力的同时具有低免疫治疗应答以及转移倾向。轨迹分析结果显示高SCP2表达的上皮细胞可能具有更高的恶性程度，同时SCP2可能是前列腺恶性上皮细胞分化的关键标志基因。进一步的孟德尔随机化结果显示，SCP2和PCa的发生发展具有显著的因果关系(OR=1.045,95%CI:1.010～1.083,P=0.011)。结论:通过联合单细胞转录组和孟德尔随机化，证实了SCP2基因在PCa发生发展中的作用，并为PCa治疗提供了新的靶点和治疗方向。更多还原

【Abstract】 Objective: To investigate the relationship between the lipid metabolism-related gene sterol carrier protein 2(SCP2) and prostate cancer(PCa) from a multi-omics perspective using single-cell transcriptomes combined with Mendelian randomization. Methods: Single-cell transcriptome data of benign and malignant prostate tissues were obtained from GSE120716, GSE157703 and GSE141445 datasets, respectively. Integration, quality control and annotation were performed on the data to categorize the epithelial cells into high and low SCP2 expression groups, followed by further differential and trajectory analyses. Single nucleotide polymorphism(SNP) data for SCP2 expression quantitative trait loci(eQTL) were subsequently downloaded from Genotype-Tissue Expression(GTEx) and investigated from the PCa Society Cancer-Related Genomic Alteration Panel for the Investigation of Cancer-Related Alterations(PRACTICAL) to obtain PCa outcome data for Mendelian randomization analysis to validate the causal relationship between SCP2 and PCa. Results: High SCP2-expressing epithelial cells had higher energy metabolism and proliferation capacity with low immunotherapy response and metastatic tendency. Trajectory analysis showed that epithelial cells with high SCP2 expression may have a higher degree of malignancy, and SCP2 may be a key marker gene for differentiation of malignant epithelial cells in the prostate. Further Mendelian randomization results showed a significant causal relationship between SCP2 and PCa development(OR=1.045, 95% CI: 1.010-1.083, P=0.011). Conclusion: By combining single-cell transcriptome and Mendelian randomization, the role of the lipid metabolism-related gene SCP2 in PCa development has been confirmed, and new targets and therapeutic directions for PCa treatment have been provided.更多还原