Reduced USP33 expression in gastric cancer decreases inhibitory effects of Slit2-Robo1 signalling on cell migration and EMT
Reduced USP33 expression in gastric cancer decreases inhibitory effects of Slit2-Robo1 signalling on cell migration and EMT
复制标题
胃癌中 USP33 表达减少可降低 Slit2→Robo1 信号对细胞迁移和 EMT 的抑制作用
DOI：
10.1111/cpr.12606
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发表时间：
2019
影响因子：
8.5
通讯作者：
Xu Zekuan
中科院分区：
文献类型：
--
作者：
Xia Yiwen;Wang Linjun;Xu Zhipeng;Kong Ruirui;Wang Fei;Yin Kai;Xu Jianghao;Li Bowen;He Zhongyuan;Wang Lu;Xu Hao;Zhang Diancai;Yang Li;Wu Jane Y.;Xu Zekuan
胃癌是世界上最常见的恶性肿瘤之一，每年造成大量的死亡。Slit‐Robo信号通路最初因其在神经元引导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的肿瘤侵袭和转移。然而，Slit-Robo信号转导的作用及其在胃癌发病机制中的分子机制仍有待阐明。材料和方法Slit 2，Robo 1和USP 33表达分析数据集从Oncomine数据库和测量在人类胃癌标本。在体外和体内研究了Slit 2-Robo 1-USP 33信号传导对胃癌细胞迁移和上皮-间质转化（EMT）的作用。Robo 1和USP 33之间的相互作用的机制进行了探讨，通过co-IP和泛素化蛋白analysis.ResultsThe Slit 2和Robo 1的mRNA和蛋白水平较低，在GC组织相对于那些在相邻的健康组织。重要的是，Slit 2以Robo依赖性方式抑制GC细胞迁移并抑制EMT过程。Slit 2 ‐ Robo 1的抑制功能由泛素特异性蛋白酶33（USP 33）介导，通过去泛素化和稳定Robo 1。USP 33在GC组织中的表达降低，USP 33水平降低与患者生存率低相关。ConclusionsOur study revealed the inhibitory function of Slit‐Robo signaling in GC and uncovered a role of USP 33 in suppressing cancer cell migration and EMT by enhancing Slit 2 ‐ Robo 1 signaling. USP 33代表了作为GC预后生物标志物的可行选择。
ObjectivesGastric 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.Materials and methodsSlit2, 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.ResultsThe 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.ConclusionsOur 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.