RESULTS: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect.
CONCLUSIONS: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.
结果:在这项研究中,我们首先报道了PC组织中PSMD7的频繁过表达,高水平的PSMD7与PC患者的较短生存期和恶性表型显著相关。一系列体外和体内功能获得/丧失测试表明PSMD7促进PC细胞的进展。此外,我们发现PSMD7通过激活Notch同源物1(Notch1)信号促进PC细胞进展。有趣的是,在PC细胞中,PSMD7敲低对细胞过程的抑制作用与Notch1敲低时观察到的效果相当。机械上,PSMD7去泛素化和稳定化性别决定区Y(SRY)-盒2(SOX2),Notch1信号的关键调解人。由PSMD7介导的SOX2的稳定化显著增加了SOX2蛋白水平,随后激活Notch1途径。最后,SOX2表达的恢复消除了PSMD7沉默的抗肿瘤作用。
结论:综合来看,我们的工作通过增强SOX2介导的Notch1信号通路,鉴定并验证了PSMD7作为PC进展的启动子.这一发现表明PSMD7有望作为治疗这种难治性疾病的潜在治疗靶标。