TNFAIP2 promotes NF-κB signaling mediate lymph node metastasis of oral squamous cell carcinoma by protecting IKKβ from ubiquitin proteasome degradation

作者：Xu Teng, Yaning Wang, Zechen Zhao, Jinsong Wang, Zhenyuan Zhao, Yuemei Yang, Xiaomeng Song, Qingguo Lai · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02077-3 · 被引用次数：13 · 研究领域：NF-κB Signaling Pathways、Cell death mechanisms and regulation、Ubiquitin and proteasome pathways

BACKGROUND: Tumor dissemination is a life-threatening event which confers to most cancer-related deaths with limited effective therapeutic option. TNFα-induced protein 2 (TNFAIP2) reveals pro-metastasis potential in several cancers. However, its definite role and underlying mechanism in oral squamous cell carcinoma (OSCC) is largely unknown. METHODS: The impact of TNFAIP2 on tumor metastasis was assessed based on the conditional knockout mouse with 4-nitroquinoline-1-oxide (4NQO) induced OSCC model through feature and immunohistochemistry analysis. To explore the specific mechanism, enrichment analysis and co-immunoprecipitation were applied. Meanwhile, the nano-hydroxyapatite (nHAp) and poly-L-lysine (PLL) based RNA interference delivery system was designed to restrict tumor dissemination. RESULTS: The conditional knockout Tnfaip2 in epithelium reduced tumor initiation rate, differentiation degree and cervical lymph node metastasis (LNM) in mouse exposed to 4NQO. Enrichment analysis suggested nuclear factor-kappa B (NF-κB) signaling was associated with these effects. Western blot proved that TNFAIP2 prevented the ubiquitin proteasome degradation of inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ), a classical transcriptional activator protein in NF-κB signaling. Mechanistically, TNFAIP2 was demonstrated to competitively interact with kelch-like ECH-associated protein 1 (KEAP1) to avoid IKKβ from ubiquitination at K63 and proteasomal degradati...