Sialylated Immunoglobulin G Promotes the Malignant Progression of Oral Squamous Cell Carcinoma through VCP-Mediated NDUFB6 Stabilization Regulated Mitochondrial Oxidative Phosphorylation.

The absence of distinct biomarkers for oral squamous cell carcinoma (OSCC) hampers clinical diagnosis and treatment. Previous studies have demonstrated that sialylated immunoglobulin G (SIA-IgG) is up-regulated in a variety of epithelial-derived tumors and plays an important biological role. However, the function of SIA-IgG in OSCC progression is yet to be clarified. The expression characteristics and clinical significance of SIA-IgG were investigated using immunohistochemistry, western blot, and bioinformatics analysis. The biological functions of SIA-IgG were evaluated in vitro and in vivo. The underlying mechanisms of SIA-IgG in OSCC were elucidated using immunoprecipitation, mass spectrometry, and proteomic profiling. Furthermore, we explored the inhibitory effects of an exogenously added SIA-IgG-specific monoclonal antibody, RP215, on OSCC. An elevated level of SIA-IgG was observed in OSCC, and this was linked to poor survival among OSCC patients. Meanwhile, the up-regulation of SIA-IgG and valosin-containing protein (VCP) promoted the malignant progression of OSCC by activating the oxidative phosphorylation pathway. Moreover, SIA-IgG showed potential as a marker of OSCC cancer stem cells. Mechanistically, SIA-IgG enhanced the interaction between VCP and NADH:ubiquinone oxidoreductase subunit B6 (NDUFB6), thereby inhibiting the ubiquitin-proteasome-pathway-mediated degradation of NDUFB6 and sustaining the activation of the oxidative phosphorylation pathway. This inhibitory effect was abrogated by the overexpression of VCP. Furthermore, the SIA-IgG-specific antibody RP215 suppressed the malignant progression of OSCC, both in vitro and in vivo.