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Journal of Peking University (Health Sciences) ›› 2025, Vol. 57 ›› Issue (4): 633-643. doi: 10.19723/j.issn.1671-167X.2025.04.002

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Multi-omics analysis of the relationship between oxidative stress-related gene and prostate cancer

Jiaxin NING1,2, Haoran WANG1,2, Shuhang LUO1,2, Jibo JING1,2, Jianye WANG1,2, Huimin HOU1,*(), Ming LIU1,2,*()   

  1. 1. Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Beijing 100005, China
    2. Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China
  • Received:2025-01-26 Online:2025-08-18 Published:2025-08-02
  • Contact: Huimin HOU, Ming LIU
  • Supported by:
    Beijing Natural Science Foundation(7232138)

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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

CLC Number: 

  • R737.25

Figure 1

Association between methylation levels of oxidative stress-related genes and prostate cancer risk in summary-data-based Mendelian randomization (SMR) analysis"

Figure 2

Manhattan plot of different oxidative stress-related genes and their methylation sites"

Figure 3

Association between the expression of oxidative stress-related genes and prostate cancer A, relationship between the expression of oxidative stress-related genes and prostate cancer in Mendelian randomization analysis; B, Manhattan plot of oxidative stress-related gene expression with statistically significant associations."

Table 1

Oxidative stress-related genes significantly associated with prostate cancer in the GTEx database"

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

Figure 4

Association between circulating protein levels of oxidative stress-related genes and prostate cancer A, relationship between oxidative stress-related circulating proteins and prostate cancer in Mendelian randomization analysis; B, Manhattan plot of oxidative stress-related proteins with statistically significant associations."

Table 2

Circulating proteins significantly associated with prostate cancer in the deCODE database"

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

Figure 5

Knockdown of SCP2 suppresses the oncogenic phenotype of prostate cancer cells and promotes apoptosis A, siRNA treatment of C4-2 cells significantly decreased SCP2 protein expression (* * * *P < 0.000 1); B, knockdown of SCP2 significantly reduced the proliferative capacity of C4-2 cells (* * * *P < 0.000 1); C, D, knockdown of SCP2 markedly suppressed the migration and invasion abilities of C4-2 cells (* * * *P < 0.000 1); E, knockdown of SCP2 increased the expression of apoptotic markers CASP3 (* *P < 0.01 & *P < 0.05) and PARP (* * *P < 0.001 & *P < 0.05) in C4-2 cells."

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