The Vascular Endothelial Growth Factor A–Vascular Endothelial Growth Factor Receptor 2 Axis Drives Malignant Potential in Oral Squamous Cell Carcinoma by Promoting Stemness and Cell Proliferation

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with poor clinical outcomes driven by metastasis and recurrence. Vascular endothelial growth factor receptor 2 (VEGFR2), a key mediator of vascular endothelial growth factor A (VEGFA)-dependent angiogenesis, has recently been implicated in tumor cell-intrinsic signaling; however, its role in OSCC remains unclear. This study investigated VEGFA-VEGFR2 signaling in OSCC using a 4-nitroquinoline 1-oxide-induced mouse carcinogenesis model and human tissue specimens. Spatial transcriptomic analysis of murine tongues demonstrated enrichment of Kdr (Vegfr2) and Vegfa expression in tumor regions. Immunohistochemical analyses demonstrated up-regulation of VEGFR2, particularly nuclear VEGFR2, during tumor development. Exogenous VEGFA increased VEGFR2 expression and induced its nuclear localization in murine carcinoma cells. In human tongue squamous cell carcinoma, VEGFR2 was localized in the cytoplasm and nucleus, and nuclear VEGFR2 expression was significantly associated with tumor stage, lymph node metastasis, and proliferative activity. Nuclear VEGFR2 expression also correlated with VEGFA expression in epithelial and stromal compartments. Functional analyses showed that VEGFA-VEGFR2 signaling enhanced cell migration and stem-like properties independently of angiogenesis. These findings indicate that nuclear VEGFR2 reflects pathway activation and contributes to tumor aggressiveness, highlighting its potential as a biomarker and therapeutic target.