N-glycosylation stabilized TNFAIP6 promotes ovarian cancer metastasis by activating the PI3K-AKT signaling pathway

Abstract

Background

Ovarian cancer (OC) represents the most lethal gynecological malignancy, with a dismal 5-year survival rate of ∼30 % in advanced-stage patients, largely due to metastatic dissemination and limited therapeutic options. Elucidating the molecular drivers of OC metastasis remains imperative for developing targeted interventions.

Methods

Integrative multi-omics analyses were performed using bulk RNA-seq and scRNA-seq data from TCGA and GEO repositories. Protein dynamics were validated via Western blot and immunofluorescence. Prognostic significance was assessed through Kaplan-Meier survival analysis with log-rank tests. Functional characterization of TNFAIP6 was achieved through lentivirus-mediated shRNA knockdown/overexpression, complemented by in vitro assays and in vivo metastasis models. The ubiquitination levels of TNFAIP6 were detected through Co-IP experiments. Immune cell infiltration was quantified via computational deconvolution algorithms.

Results

TNFAIP6 emerged as a metastasis-associated oncogene, with elevated expression correlating significantly with poor prognoses. Mechanistically, N-glycosylation stabilized TNFAIP6 by impeding ubiquitin-proteasomal degradation. TNFAIP6 knockdown genetically attenuated OC cell invasion, migration, and peritoneal dissemination. Pathway analyses revealed TNFAIP6-driven activation of the PI3K/AKT signaling pathway, which orchestrated epithelial-mesenchymal transition. Notably, TNFAIP6 upregulation was significantly correlated with tumor immune-suppressing microenvironment and predicted resistance to immune checkpoint inhibitors and chemotherapy.

Conclusions

Our study establishes TNFAIP6 as a critical regulator of OC metastasis via PI3K/AKT pathway activation and a biomarker of therapeutic resistance. Targeting TNFAIP6 may offer dual strategies to counteract metastatic progression and therapeutic resistance in OC.