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YTHDC2 Upregulated by Tumor Necrosis Factor-α Promotes Gastric Cancer Cell Migration and Invasion
Vol 38, Issue 3, 2024
Abstract
Background: The expression of YTH domain-containing protein 2 (YTHDC2) has been reported to be elevated in various types of cancers, but its underlying mechanism of action remains unclear. In gastric cancer patients, YTHDC2 levels in tissues exhibit positive correlation with tumor invasion and recurrence. Tumor necrosis factor-α (TNF-α), produced by both cancer cells and the tumor microenvironment, exerts pleiotropic effects on tumorigenesis and tumor progression. Herein, we investigated the roles of YTHDC2 in inducing gastric cancer (GC) cell proliferation and metastasis due to TNF-α. Methods: GC cells were exposed to TNF-α followed by transfection with small interfering RNAs (siRNAs) si-NC, si-YTHDC2#1, si-YTHDC2#2, si-YTHDC2#1+vector or si-YTHDC2#1+OE-ZEB1 into human GC cell lines. These interventions aimed to knock down YTHDC2 or induce the overexpression of Zinc finger E-box-binding homeobox 1 (ZEB1). Various assays, including clone formation, transwell migration, cell counting kit-8 (CCK8) viability, western blot analysis, and wound healing, were conducted to elucidate the underlying mechanisms through which GC cells regulate YTHDC2. Furthermore, a murine heterotopic tumor model was employed to validate YTHDC2 functions. Results: The results showed that YTHDC2 was overexpressed in GC tissues and cells and TNF-α could induce YTHDC2 expression in GC cells. Knocking down YTHDC2 inhibited the proliferation and metastasis of GC cells following TNF-α exposure. Moreover, silencing YTHDC2 suppressed GC cell progression through Hypoxia-inducible factor 1-alpha (HIF-1α)/ZEB1 activation. These findings were confirmed in a murine heterotopic tumor model, where YTHDC2 suppression attenuated tumor growth in vivo. Conclusions: It was concluded that the expression of YTHDC2 may modulate the tumorigenesis and metastasis of GC. At the same time, targeting both YTHDC2 and ZEB1 may be a promising strategy for GC management.
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Copyright (c) 2024 Wenke Yin, Xiaoyan Song, Yue Xiang, Linli He
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy