Background

Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC).

Methods

Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors.

Results

Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3β/β-catenin signaling pathway and the accumulation of β-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3β/β-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced atrophic gastritis and gastric tumorigenesis.

Conclusion

These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3β/β-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.

中文翻译：

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EPRS/GluRS通过WNT/GSK-3β/β-catenin信号通路促进胃癌发展

背景

谷氨酰-脯氨酰-tRNA 合成酶 (EPRS/GluRS) 是多合成酶复合物的主要组成部分，可能在癌症发展中起关键作用。然而，EPRS的生物学功能、分子机制和抑制剂在胃癌（GC）中的作用尚未得到研究。

方法

进行免疫组织化学检测EPRS在人胃肿瘤组织中的表达。通过敲除EPRS、细胞源性异种移植小鼠模型和患者源性异种移植小鼠模型来鉴定EPRS的生物学功能。应用免疫沉淀来阐明 EPRS 和 SCYL2 之间的相互作用。进行计算机对接模型和多次体外和体内实验以发现EPRS抑制剂。

结果

在这里，我们报告 EPRS 在 GC 组织中经常过表达，与相邻的对照相比，它的过表达预示着 GC 患者的不良预后。在功能上，EPRS 的高表达与体外和体内的 GC 发展呈正相关。机制上，EPRS 直接与 SCYL2 结合以增强 WNT/GSK-3β/β-catenin 信号通路的激活和 β-catenin 在细胞核中的积累，导致 GC 细胞增殖和肿瘤生长。此外，我们发现黄当归醇 (XA) 和 4-羟基德里霉素 (4-HD) 可以直接与 EPRS 结合，从而阻断 WNT/GSK-3β/β-catenin 信号通路。更重要的是，XA 和 4-HD 抑制胃癌患者来源的异种移植肿瘤生长和幽门螺杆菌合并酒精性萎缩性胃炎和胃肿瘤发生。

结论

这些发现揭示了一种通过靶向 EPRS 介导的 WNT/GSK-3β/β-连环蛋白级联反应来预防和治疗 GC 的有前景的策略。此外，XA 和 4-HD 可能是用于 GC 预防和治疗的有效试剂。