NEK2 Promotes OSCC Invasion and Metastasis by Activating TNF ‐α Signaling Through Impairment of Desmosomal Adhesion

ABSTRACT

NIMA‐related kinase 2 (NEK2) is a cell cycle regulator aberrantly overexpressed in multiple cancers, yet its non‐mitotic roles in oral squamous cell carcinoma (OSCC) invasion and metastasis remain unclear. Here, we analyzed public transcriptomic and single‐cell datasets and found that NEK2 is significantly upregulated in OSCC tissues, with higher expression in cases exhibiting lymph node metastasis and associations with poor prognosis. Functional assays demonstrated that NEK2 promotes OSCC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Transcriptomic and pathway analyses revealed that NEK2 activates TNF‐α inflammatory signaling, and rescue experiments confirmed that the pro‐invasive effects of NEK2 are largely dependent on TNF‐α pathway activation. Through immunoprecipitation–mass spectrometry, we identified three core desmosomal proteins—desmoplakin (DSP), desmoglein‐1 (DSG1), and junction plakoglobin (JUP)—as novel NEK2‐interacting partners. NEK2 binding impaired desmosomal adhesion function at cell–cell junctions, and DSP overexpression partially rescued NEK2‐induced TNF‐α secretion, EMT, and invasion. In vivo, NEK2 knockdown suppressed xenograft tumor growth, preserved junctional desmosomal protein localization, and downregulated TNF‐α target genes. Collectively, our findings uncover a NEK2–desmosome–TNF‐α signaling axis that drives OSCC invasion and metastasis, providing new mechanistic insights and highlighting NEK2 as a potential therapeutic target.