TIPE2 inhibits the migration and invasion of epithelial ovarian cancer cells by targeting Smad2 to reverse TGF ‐β1‐induced EMT

Abstract Epithelial ovarian cancer is the deadliest gynecologic malignancy, characterized by high metastasis. Transforming growth factor‐β1 (TGF‐β1) drives epithelial‐ mesenchymal transformation (EMT), a key process in tumor metastasis. Tumor necrosis factor‐α‐induced protein 8 (TNFAIP8)‐like 2 (TIPE2) acts as a negative regulator of innate and adaptive immunity and involves in various cancers. However, its relationship with TGF‐β1 in ovarian cancer and its role in reversing TGF‐β1‐induced EMT remain unclear. This study examined TIPE2 mRNA and protein expression using quantitative RT‐PCR (qRT‐PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of epithelial ovarian cancer cells were assessed through 5‐ethynyl‐2‐deoxyuridine, colony‐forming, transwell migration and invasion assays. The relationship between TIPE2 and TGF‐β1 was investigated using qRT‐PCR and enzyme‐linked immunosorbent assay, while the interaction between TIPE2 and Smad2 was identified via co‐immunoprecipitation. The results revealed that TIPE2 protein was significantly down‐regulated in epithelial ovarian cancer tissues and correlated with the pathological type of tumor, patients' age, tumor differentiation degree and FIGO stage. TIPE2 and TGF‐β1 appeared to play an opposite role to each other during the progression of human ovarian cancer cells. Furthermore, TIPE2 inhibited the metastasis and EMT of ovarian cancer cells by combining with Smad2 in vitro or in an intraperitoneal metastasis model. Consequently, these findings suggest that TIPE2 plays a crucial inhibitory role in ovarian cancer metastasis by modulating the TGF‐β1/Smad2/EMT signaling pathway and may serve as a potential target for ovarian cancer, providing important direction for future diagnostic and therapeutic strategies.