氧化应激相关基因与前列腺癌关系的多组学分析

doi:10.19723/j.issn.1671-167X.2025.04.002

摘要/Abstract

摘要：

目的: 利用基于汇总数据的孟德尔随机化(summary-data-based Mendelian randomization, SMR)、共定位分析和细胞实验, 从多组学角度研究氧化应激相关基因与前列腺癌(prostate cancer, PCa)之间的关系。方法: 对基因甲基化、基因表达和循环蛋白质的汇总级数据在下载后进行筛选, 将PRACTICAL队列作为观察队列, deCODE数据库作为验证队列, 使用SMR分析和依赖性工具异质性(heterogeneity in dependent instruments, HEIDI)检验评估氧化应激相关基因与PCa的关联性和异质性, 采用共定位分析确定氧化应激相关基因与PCa之间是否存在共享突变。进一步对筛选出的基因采用CCK-8、细胞划痕实验、Transwell侵袭实验、蛋白免疫印迹实验探究其对PCa细胞系C4-2生物学行为的影响。结果: 经过多组学分析, SCP2在基因甲基化、基因表达和循环蛋白质层面均被确定为与PCa风险增加存在显著关联性, 而GSTP1在基因甲基化和循环蛋白质层面, LPO在循环蛋白质层面被认为与PCa风险增加存在显著关联。在基因甲基化层面, SCP2的cg00581603(OR=1.11, 95%CI: 1.05~1.17)和cg13078931(OR=1.12, 95%CI: 1.05~1.18)甲基化被认为是PCa的致病因素; GSTP1的cg05244766(OR=0.89, 95%CI: 0.84~0.95)甲基化被认为是PCa的保护因素。在基因表达层面, SCP2(OR=1.05, 95%CI: 1.02~1.07)同样被确定为PCa的致病因素。在循环蛋白质层面, SCP2(OR=2.10, 95%CI: 1.34~3.29)显示出了与基因甲基化和基因表达层面一致的PCa致病趋势, 此外, GSTP1(OR=1.16, 95%CI: 1.07~1.25)和LPO(OR=1.12, 95%CI: 1.05~1.19)都与PCa风险增加显著相关。进一步的细胞实验表明, 敲除SCP2能显著降低PCa细胞的致癌表型。结论: 通过多组学分析和细胞实验验证, 本研究证实了SCP2与PCa发生风险增加之间存在显著关联性, 这一发现加深了对PCa发病机制的了解, 并为PCa治疗提供了新的靶点和治疗方向。

关键词: 孟德尔随机化分析, 前列腺肿瘤, 氧化应激, 多组学分析

Abstract:

Objective: To investigate the relationship between oxidative stress-related genes and prostate cancer (PCa) from a multi-omics perspective using summary-data-based Mendelian randomization (SMR), colocalization analysis, and cellular experiments. Methods: Summary-level data on DNA methylation, gene expression, and circulating proteins were obtained and filtered. The PRACTICAL consortium was used as the discovery cohort, with the deCODE database serving as the validation cohort. SMR analysis and heterogeneity in dependent instruments (HEIDI) tests were conducted to assess the association and heterogeneity between oxidative stress-related genes and PCa. Colocalization analysis was performed to determine whether oxidative stress-related genes and PCa shared common causal variants. Finally, CCK-8 assays, wound healing assays, and Transwell invasion assays and Western blotting, were conducted to examine the effects of oxidative stress-related genes on the biological behavior of the PCa cell line C4-2. Results: Multi-omics analysis identified SCP2 as significantly associated with increased PCa risk across gene methylation, gene expression, and circulating protein levels. GSTP1 showed significant associations at the methylation and protein levels, while LPO was associated at the protein level. At the methylation level, SCP2 sites cg00581603 (OR=1.11, 95%CI: 1.05-1.17) and cg13078931 (OR=1.12, 95%CI: 1.05-1.18) were identified as pathogenic. Among the four methylation sites in GSTP1, only cg05244766 (OR=0.89, 95%CI: 0.84-0.95) was considered protective. At the gene expression level, SCP2 (OR=1.05, 95%CI: 1.02-1.07) was also found to be a pathogenic factor. At the circulating protein level, SCP2 (OR=2.10, 95%CI: 1.34-3.29) showed a consistent pathogenic trend. In addition, GSTP1 (OR=1.16, 95%CI: 1.07-1.25) and LPO (OR=1.12, 95%CI: 1.05-1.19) were significantly associated with increased PCa risk. Further functional assays demonstrated that knockdown of SCP2 significantly reduced the oncogenic phenotype of prostate cancer cells. Conclusion: Through integrated multi-omics analysis and experimental validation, this study confirmed a significant association between SCP2 and increased PCa risk. These findings enhance our understanding of PCa pathogenesis and provide new potential targets and therapeutic directions for PCa treatment.

Key words: Mendelian randomization analysis, Prostatic neoplasms, Oxidative stress, Multi-omics analysis

中图分类号:

R737.25

宁家昕, 王浩然, 罗书航, 敬吉波, 王建业, 侯惠民, 刘明. 氧化应激相关基因与前列腺癌关系的多组学分析[J]. 北京大学学报（医学版）, 2025, 57(4): 633-643.

Jiaxin NING, Haoran WANG, Shuhang LUO, Jibo JING, Jianye WANG, Huimin HOU, Ming LIU. Multi-omics analysis of the relationship between oxidative stress-related gene and prostate cancer[J]. Journal of Peking University (Health Sciences), 2025, 57(4): 633-643.

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Gene	OR	95%CI	P
COX6B1	1.16	1.059-1.261	0.032
BAK1	0.95	0.915-0.981	0.047
TXN	1.13	1.041-1.218	0.047
PLA2G2A	1.05	1.015-1.081	0.047

Protein	OR	95%CI	P
LPO	0.97	0.947-0.983	0.009
HSPA1A	0.97	0.948-0.983	0.009
PLA2G2A	1.03	1.011-1.053	0.049

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