A20 enhances the migration and metastasis of gastric cancer cells by promoting occludin degradation.

Chronic inflammation is a well-established risk factor in the development of gastric cancer (GC). Tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) is an inflammation-associated protein that functions as an oncogene in various cancers, but the role of A20 in GC progression remains unclear. In this study, clinical analyses revealed that elevated A20 expression in GC patients was significantly associated with increased tumor aggressiveness and metastatic potential. Functionally, A20 overexpression enhanced GC cell migration, whereas its knockdown suppressed this effect. Moreover, A20 promoted epithelial-mesenchymal transition and reduced the tight junction protein occludin. Mechanistically, A20 induced occludin endocytosis and lysosomal degradation via its ovarian tumor (OTU) domain. Pull-down assays revealed that A20 interacts with the migration-related protein RhoA, increasing its stability and thereby sustaining ROCK2 phosphorylation, which contributes to occludin degradation. PLA further showed that mutation of the OTU domain disrupted the interaction between A20 and RhoA in AGS cells, indicating the necessity of the OTU domain for this interaction. In conclusion, our findings demonstrate that A20 promotes GC cell migration by stabilizing RhoA and facilitating occludin degradation, underscoring A20 as a potential therapeutic target to inhibit GC metastasis.