Journal of gastroenterology and hepatology · 2026
METTL1-Mediated m7G Modification of GINS2 mRNA Activates STAT3 to Drive Esophageal Squamous Cell Carcinoma Progression.
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Han Wu, Shen Zhimin, Zhang Peipei
Аннотация
BACKGROUND: METTL1-mediated m7G modification plays a procancer role in various malignant tumors, but whether it promotes the progression of esophageal squamous cell carcinoma (ESCC) by regulating the DNA replication factor GINS2 and tumor-associated macrophage polarization remains unclear.
METHODS: The expression and function of GINS2 were examined through in vitro and in vivo experiments. RIP, MeRIP, and RNA stability assays were used to validate the regulatory effect of METTL1 on GINS2 modification. The impact on macrophage polarization was explored using a coculture system and STAT3 agonist Colivelin rescue experiments.
RESULTS: GINS2 was highly expressed in ESCC. Knockdown of GINS2 inhibited the malignant phenotypes of tumor cells and reversed epithelial-mesenchymal transition (EMT). Mechanistically, METTL1 enhanced the stability of GINS2 mRNA through m7G modification, thereby activating the STAT3 pathway and inducing M2 polarization of macrophages. The STAT3 agonist Colivelin partially reversed the tumor-suppressive effects induced by GINS2 knockdown. In vivo knockdown of GINS2 suppressed tumor growth and M2 infiltration.
CONCLUSION: METTL1-mediated m7G modification stabilizes GINS2 mRNA, activates the STAT3 pathway, induces M2 polarization, and promotes ESCC progression. This axis provides a novel potential diagnostic and therapeutic target for ESCC.
METHODS: The expression and function of GINS2 were examined through in vitro and in vivo experiments. RIP, MeRIP, and RNA stability assays were used to validate the regulatory effect of METTL1 on GINS2 modification. The impact on macrophage polarization was explored using a coculture system and STAT3 agonist Colivelin rescue experiments.
RESULTS: GINS2 was highly expressed in ESCC. Knockdown of GINS2 inhibited the malignant phenotypes of tumor cells and reversed epithelial-mesenchymal transition (EMT). Mechanistically, METTL1 enhanced the stability of GINS2 mRNA through m7G modification, thereby activating the STAT3 pathway and inducing M2 polarization of macrophages. The STAT3 agonist Colivelin partially reversed the tumor-suppressive effects induced by GINS2 knockdown. In vivo knockdown of GINS2 suppressed tumor growth and M2 infiltration.
CONCLUSION: METTL1-mediated m7G modification stabilizes GINS2 mRNA, activates the STAT3 pathway, induces M2 polarization, and promotes ESCC progression. This axis provides a novel potential diagnostic and therapeutic target for ESCC.