Study on the mechanism of radiotherapy in suppression of nasopharyngeal carcinoma based on FOXC2/CXCL12/CXCR4 axis

Objective Nasopharyngeal carcinoma (NPC) is a malignant tumor with unique geographical distribution characteristics. Although radiotherapy is its core treatment modality, drug resistance to radiotherapy and systemic metastasis remain significant clinical challenges. This study aims to investigate the molecular interaction mechanisms of the transcriptional regulatory factor FOXC2/CXCL12/CXCR4 signaling pathway in the pathogenesis, radiotherapy sensitivity, and bone metastasis of NPC. Methods This study integrated computational analysis of open datasets with cellular experiments. Transcriptomic analysis was performed to compare the expression levels of FOXC2 in nasopharyngeal carcinoma tissues versus their normal control tissues. Single-cell RNA sequencing technology was employed to precisely map the expression profile of FOXC2 in tumor epithelial cell populations. Gene manipulation was used to suppress or enhance FOXC2 expression in nasopharyngeal carcinoma cell models to evaluate its effects on cell growth, motility, invasiveness, and response to radiotherapy. Results The expression levels of FOXC2 were markedly elevated in nasopharyngeal carcinoma specimens, with its localization primarily observed within malignant epithelial cells. Genetic silencing of FOXC2 led to significant impairment in the proliferative capacity, migratory potential, and invasive properties of NPC cells. Conversely, forced expression of this transcription factor reversed the suppressive effects induced by radiation treatment. At the molecular level, FOXC2 was found to stimulate the CXCL12/CXCR4 signaling cascade, as evidenced by increased CXCR4 expression and enhanced chemokine pathway activity in FOXC2-positive cell populations. Furthermore, FOXC2 demonstrated regulatory effects on indicators of bone remodeling, implying its involvement in osseous metastatic processes. Conclusion Our research reveals that FOXC2 suggests tumor advancement and confers resistance to radiation therapy in NPC through its regulation of the CXCL12/CXCR4 signaling network and associated chemotactic pathways. This study identifies the FOXC2/CXCL12/CXCR4 molecular axis as a promising intervention point for developing novel strategies to combat radiotherapy insensitivity and prevent metastatic spread in nasopharyngeal carcinoma cases.