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EPRS/GluRS promotes gastric cancer development via WNT/GSK-3ß/ß-catenin signaling pathway.
Liu, Hui; Fredimoses, Mangaladoss; Niu, Peijia; Liu, Tingting; Qiao, Yan; Tian, Xueli; Chen, Xiaobing; Kim, Dong Joon; Li, Xiang; Liu, Kangdong; Dong, Zigang.
Afiliación
  • Liu H; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Fredimoses M; China-US (Henan) Hormel Cancer Institute, Jinshui District, No.127, Dongming Road, Zhengzhou, 450008, Henan, China.
  • Niu P; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Liu T; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Qiao Y; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Tian X; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Chen X; Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No.127, Dongming Road, Jinshui District, Zhengzhou, 450008, Henan, China.
  • Kim DJ; China-US (Henan) Hormel Cancer Institute, Jinshui District, No.127, Dongming Road, Zhengzhou, 450008, Henan, China.
  • Li X; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
  • Liu K; China-US (Henan) Hormel Cancer Institute, Jinshui District, No.127, Dongming Road, Zhengzhou, 450008, Henan, China.
  • Dong Z; Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.
Gastric Cancer ; 24(5): 1021-1036, 2021 09.
Article en En | MEDLINE | ID: mdl-33740160
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-3ß/ß-catenin signaling pathway and the accumulation of ß-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-3ß/ß-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-3ß/ß-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Beta Catenina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Gastric Cancer Asunto de la revista: GASTROENTEROLOGIA / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Japón
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Beta Catenina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Gastric Cancer Asunto de la revista: GASTROENTEROLOGIA / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Japón