Current treatments including androgen deprivation fail to prevent prostate cancer (PrCa) from progressing to castration‐resistant PrCa (CRPC). Accumulating evidence highlights the relevance of prostate‐specific antigen (PSA) in the development and progression of PrCa. The underlying mechanism whereby PSA functions in PrCa, however, has yet been elucidated. We demonstrated that PSA knockdown attenuated tumorigenesis and metastasis of PrCa C4‐2 cells in vitro and in vivo, whereas promoted the apoptosis in vitro. To illuminate the comprehensive role of PSA in PrCa, we performed an isobaric tag for relative and absolute quantitation (iTRAQ)‐based proteomic analysis to explore the proteomic change induced by PSA knockdown. Among 121 differentially expressed proteins, 67 proteins were up‐regulated, while 54 proteins down‐regulated. Bioinformatics analysis was used to explore the mechanism through which PSA exerts influence on PrCa. Protein‐protein interaction analysis showed that PSA may mediate POTEF, EPHA3, RAD51C, HPGD and MCM4 to promote the initiation and progression of PrCa. We confirmed that PSA knockdown induced the up‐regulation of MCM4 and RAD51C, while it down‐regulated POTEF and EPHA3; meanwhile, MCM4 was higher in PrCa para‐cancerous tissue than in cancerous tissue, suggesting that PSA may facilitate the tumorigenesis by mediating MCM4. Our findings suggest that PSA plays a comprehensive role in the development and progression of PrCa.

中文翻译：

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蛋白质组学分析确定前列腺特异性抗原在前列腺癌中的全面作用

目前包括雄激素剥夺在内的治疗均无法阻止前列腺癌（PrCa）发展为去势抵抗性PrCa（CRPC）。越来越多的证据突出了前列腺特异性抗原（PSA）在PrCa发生和发展中的相关性。但是，PSA在PrCa中起作用的基本机制尚未阐明。我们证明了PSA抑制可在体外和体内减弱PrCa C4-2细胞的肿瘤发生和转移，而在体外促进其凋亡。为了阐明PSA在PrCa中的全面作用，我们对基于相对和绝对定量（iTRAQ）的蛋白质组学分析进行了同量异位标记，以探讨PSA敲低引起的蛋白质组变化。在121种差异表达的蛋白质中，有67种蛋白质被上调，而54种蛋白质被下调。使用生物信息学分析来探索PSA对PrCa产生影响的机制。蛋白质-蛋白质相互作用分析表明，PSA可能介导POTEF，EPHA3，RAD51C，HPGD和MCM4促进PrCa的启动和发展。我们证实PSA抑制可诱导MCM4和RAD51C上调，而下调POTEF和EPHA3。同时，PrCa癌旁组织中的MCM4高于癌组织，表明PSA可能通过介导MCM4促进肿瘤发生。我们的发现表明PSA在PrCa的发生和发展中起着全面的作用。我们证实PSA抑制可诱导MCM4和RAD51C上调，而下调POTEF和EPHA3。同时，PrCa癌旁组织中的MCM4高于癌组织，表明PSA可能通过介导MCM4促进肿瘤发生。我们的发现表明PSA在PrCa的发生和发展中起着全面的作用。我们证实PSA抑制可诱导MCM4和RAD51C上调，而下调POTEF和EPHA3。同时，PrCa癌旁组织中的MCM4高于癌组织，表明PSA可能通过介导MCM4促进肿瘤发生。我们的发现表明PSA在PrCa的发生和发展中起着全面的作用。