EPRS/GluRS promotes gastric cancer development via WNT/GSK-3β/β-catenin signaling pathway

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 24; no. 5; pp. 1021 - 1036
• Main Authors: Liu, Hui, Fredimoses, Mangaladoss, Niu, Peijia, Liu, Tingting, Qiao, Yan, Tian, Xueli, Chen, Xiaobing, Kim, Dong Joon, Li, Xiang, Liu, Kangdong, Dong, Zigang
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.09.2021; Springer Nature B.V
• Subjects: Abdominal Surgery; Amino Acyl-tRNA Synthetases; Animals; beta Catenin - metabolism; Cancer Research; Cell Line, Tumor; Cell Proliferation; Gastric cancer; Gastritis; Gastroenterology; Glutamic acid receptors; Glycogen Synthase Kinase 3 beta; Humans; Immunohistochemistry; Immunoprecipitation; Medicine; Medicine & Public Health; Mice; Oncology; Original Article; Proline-tRNA ligase; Signal transduction; Stomach Neoplasms; Surgical Oncology; tRNA; Tumorigenesis; Wnt protein; Wnt Signaling Pathway; Xenografts; β-Catenin; EPRS/GluRS; Gastric cancer; SCYL2; WNT/GSK-3β/β-catenin; Xanthoangelol and 4-hydroxyderricin
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-021-01180-x

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.