PDF(Pubmed)
Abstract：
BACKGROUND: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear.
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.
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.
摘要：
背景：泛素化是一种关键的翻译后修饰，可以用称为去泛素化酶（DUB）的酶家族逆转。据报道,去泛素化的失调导致致癌作用。作为DUBs家族的一员,蛋白酶体26S亚基非ATP酶7（PSMD7）在多种癌症中充当潜在的肿瘤促进因子。然而,PSMD7在胰腺癌（PC）中的临床意义和生物学功能尚不清楚。
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。
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。
