Department of Gastric Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Cell Prolif. 2019 May;52(3):e12606. doi: 10.1111/cpr.12606. Epub 2019 Mar 21.
Gastric cancer (GC) is one of the most common cancers in the world, causing a large number of deaths every year. The Slit-Robo signalling pathway, initially discovered for its critical role in neuronal guidance, has recently been shown to modulate tumour invasion and metastasis in several human cancers. However, the role of Slit-Robo signalling and the molecular mechanisms underlying its role in the pathogenesis of gastric cancer remains to be elucidated.
Slit2, Robo1 and USP33 expressions were analysed in datasets obtained from the Oncomine database and measured in human gastric cancer specimens. The function of Slit2-Robo1-USP33 signalling on gastric cancer cells migration and epithelial-mesenchymal transition (EMT) was studied both in vitro and in vivo. The mechanism of the interaction between Robo1 and USP33 was explored by co-IP and ubiquitination protein analysis.
The mRNA and protein levels of Slit2 and Robo1 are lower in GC tissues relative to those in adjacent healthy tissues. Importantly, Slit2 inhibits GC cell migration and suppresses EMT process in a Robo-dependent manner. The inhibitory function of Slit2-Robo1 is mediated by ubiquitin-specific protease 33 (USP33) via deubiquitinating and stabilizing Robo1. USP33 expression is decreased in GC tissues, and reduced USP33 level is correlated with poor patient survival.
Our study reveals the inhibitory function of Slit-Robo signalling in GC and uncovers a role of USP33 in suppressing cancer cell migration and EMT by enhancing Slit2-Robo1 signalling. USP33 represents a feasible choice as a prognostic biomarker for GC.
胃癌（GC）是世界上最常见的癌症之一，每年导致大量死亡。Slit-Robo 信号通路最初因其在神经元导向中的关键作用而被发现，最近已被证明可调节几种人类癌症中的肿瘤侵袭和转移。然而，Slit-Robo 信号通路的作用及其在胃癌发病机制中的作用的分子机制仍有待阐明。
在 Oncomine 数据库中获得的数据集分析 Slit2、Robo1 和 USP33 的表达，并测量人胃癌标本中的表达。研究 Slit2-Robo1-USP33 信号对胃癌细胞迁移和上皮-间充质转化（EMT）的功能在体外和体内。通过 co-IP 和泛素化蛋白分析探索 Robo1 和 USP33 之间相互作用的机制。
GC 组织中 Slit2 和 Robo1 的 mRNA 和蛋白水平均低于相邻健康组织。重要的是，Slit2 以 Robo1 依赖的方式抑制 GC 细胞迁移并抑制 EMT 过程。Slit2-Robo1 的抑制功能是通过泛素特异性蛋白酶 33（USP33）介导的，通过去泛素化和稳定 Robo1。GC 组织中 USP33 的表达减少，并且降低的 USP33 水平与患者预后不良相关。
我们的研究揭示了 Slit-Robo 信号在 GC 中的抑制功能，并揭示了 USP33 通过增强 Slit2-Robo1 信号抑制癌细胞迁移和 EMT 的作用。USP33 可作为 GC 的预后生物标志物。
