Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Department of Clinical Laboratory, General Hospital of Southern Theatre Command, Guangzhou, 510010, China.
J Exp Clin Cancer Res. 2019 Jun 24;38(1):277. doi: 10.1186/s13046-019-1270-4.
The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown.
Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models.
USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-β1 induced USP3 expression, and USP3 knockdown inhibited TGF-β1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein.
These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC.
去泛素化酶泛素特异性蛋白酶 3（USP3）在许多生物过程中发挥着关键作用。USP3 的异常表达可能在肿瘤发生发展中起着重要作用。然而，USP3 促进胃癌（GC）转移的机制在很大程度上仍不清楚。
利用蛋白质组学、RT-PCR、western blot、免疫组化、免疫荧光、细胞侵袭和迁移实验以及异种移植肿瘤模型，研究了 USP3 在体内和体外对 GC 进展的影响及其潜在机制。
GC 组织中 USP3 的表达高于匹配的正常组织，且与生存率差相关。USP3 还促进了 GC 细胞的迁移和上皮间质转化（EMT）。此外，TGF-β1 诱导 USP3 的表达，而 USP3 敲低抑制 TGF-β1 诱导的 EMT。此外，我们利用同位素标记相对和绝对定量（iTRAQ）技术，鉴定了 USP3 过表达细胞与对照细胞之间差异表达的蛋白质。重要的是，我们发现 SUZ12 是 USP3 在 GC 中发挥致癌活性所必需的。我们观察到 USP3 通过去泛素化与 SUZ12 相互作用并稳定 SUZ12。SUZ12 敲低抑制了 GC 细胞中 USP3 诱导的迁移和侵袭以及 EMT。对临床样本的检测证实，USP3 的表达与 SUZ12 蛋白的表达呈正相关，USP3 或 SUZ12 蛋白的水平与 E-钙粘蛋白蛋白的水平呈负相关。
这些发现确定了 USP3 作为一个关键的调节因子。USP3-SUZ12 轴可能促进肿瘤进展，可能成为人类 GC 的潜在治疗靶点。
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