揭示前列腺组织中与前列腺癌相关的因果蛋白标志物：一项全蛋白质组关联研究及功能验证

Background: Prostate cancer (PCa) is the second most frequently diagnosed malignancy among men. While multiple protein markers have been implicated in PCa, findings from conventional studies are often inconsistent due to methodological limitations such as selection bias and uncontrolled confounding. The proteome-wide association study (PWAS) design leverages genetic instruments to identify protein biomarkers with potential causal roles in diseases. Although candidate causal proteins in blood have been identified for PCa in our previous work, few studies have focused on prostate tissue. Methods: We conducted the first prostate tissue-based PWAS using data from the PRACTICAL/ELLIPSE consortia, comprising 122,188 PCa cases and 604,640 controls. Proteomic and genomic data were generated from 201 frozen prostate tissue samples without PCa, quantifying 11,575 proteins. We used data of 195 unrelated subjects for model building. Prediction models for protein abundance were built using nearby unambiguous SNPs of potentially associated variants, applying BLUP, LASSO, elastic net, and top1 methods. Association testing was performed for genetically predicted protein levels with PCa risk and aggressiveness. For one of the identified proteins eIF4G1, we performed knockdown of its gene expression in androgen-sensitive (LNCaP), enzalutamide-resistant LNCaP (NO-LNCaP-ENZR), and castration-resistant (22RV1) PCa cell lines, and investigated the effects on multiple phenotypes. Survival analysis was also performed using TCGA primary PCa RNA-seq data. Results: A total of 1,034 protein models achieved cross-validated R² > 0.01 and were retained for association testing. Fifty-six proteins showed significant associations with PCa risk, including 18 associated with advanced disease and seven distinguishing advanced from non-advanced cases. One of the top novel proteins, EIF4G1, is required for the initial steps of translation. Disrupting eIF4F complex activity via EIF4G1 knockdown reduced cell proliferation, colony formation, and spheroid culture growth, and decreased cell migration and invasion. EIF4G1 knockdown also sensitized LNCaP cells to enzalutamide treatment and inhibited clonogenic potential of enzalutamide-resistant cells. Pharmacological inhibition of eIF4F with SBI-756 reproduced these effects and induced G1 phase cell cycle arrest. Polysome profiling revealed decreased mRNA loading onto polysomes, indicating that knockdown of EIF4G1 impaired cap-dependent translation. Elevated expression of EIF4G1 in tumors was also associated with shorter disease-specific survival. Conclusions: Our study reveals novel prostate tissue proteins putatively causally linked to PCa risk and aggressiveness. Our functional work suggests that a novel protein, eIF4G1, presents a new target for limiting PCa progression and overcoming therapy resistance.