Increasing evidence shows that Epstein-Barr virus (
EBV) infection is closely related to various lymphoid and epithelioid
malignancies. However, the underlying mechanisms are unclear. GCNT3 (core 2β-1,6-acetylglucosaminyltransferase) is a new type of core
mucin synthase, and its expression in EBV-associated
gastric cancer (EBVaGC) is lower than that in EBV-negative
gastric cancer (EBVnGC). EBV-encoded latent
membrane protein 2A (LMP2A) is a transmembrane
protein with
tumorigenic transformation properties. Here, we demonstrated that LMP2A inhibited the transcription of GCNT3 by inhibiting Smad2/3 and Smad4. LMP2A restrained the activation of the
mTORC1 pathway by inactivating the TGF-β1/Smad pathway and then downregulated GCNT3 expression. The mTORC1-GCNT3 pathway promoted cell proliferation and migration and inhibited G0/G1 cell arrest. Related
proteins involved in epithelial-mesenchymal transition (EMT) were downstream molecules of the TGF-β1/Smad-
mTORC1-GCNT3 pathway. GCNT3 inhibited autophagy by inducing
mTORC1 phosphorylation. These findings indicate that targeting the TGF-β1/Smad-
mTORC1-GCNT3 axis may represent a novel therapeutic target in GC.ImportanceEpstein-Barr virus (EBV) is an opportunistic pathogen, and the latent
membrane protein 2A (LMP2A) encoded by EBV plays a key role in ensuring the incubation period of EBV. Glycosylation modification is an important marker of
cancer cells, and recent studies have reported that it is related to EBV. Our conclusions provide deeper theoretical support for the role of LMP2A and TGF/Smad-
mTORC1-GCNT3 in EBVaGC and help to understand glycosylation abnormalities in
cancer. Our results may provide novel therapeutic targets for the treatment of
gastric cancer against the TGF/Smad-
mTORC1-GCNT3 signaling cascade.