BMP5 mediates macrophage-driven Oral leukoplakia carcinogenesis.

Abstract

BACKGROUND AND AIMS: Oral leukoplakia (OLK) is a potentially malignant disorder of the oral cavity, and the risk of malignant transformation is positively correlated with the severity of epithelial dysplasia. This study aimed to investigate the critical role of the macrophage-BMP5 axis in OLK carcinogenesis. METHODS: We established a macrophage-depleted 4NQO-induced OLK model, and oral lesions were assessed through macroscopic and histopathological examination, immunostaining, and TUNEL staining. The target genes were identified through comparative analysis of RNA-sequencing data. Leuk1 cells were transfected with lentiviral vectors to induce BMP5 overexpression and knockdown, and cell proliferation and apoptosis were analyzed via standard in vitro functional assays. For in vivo functional validation, recombinant BMP5 protein was directly injected into the submucosa of the tongue in a 4NQO-induced OLK model. For BMP5 function in the macrophage axis, BMP5-specific siRNA was directly injected into the tongue submucosa of a 4NQO-induced OLK model with macrophage depletion. RESULTS: Macrophage depletion markedly inhibited OLK carcinogenesis, and this effect was accompanied by significant upregulation of BMP5. Furthermore, overexpression of BMP5 in the 4NQO-induced OLK model inhibited the carcinogenic progression of oral lesions, even when the macrophage population remained intact. BMP5 upregulation in Leuk1 cells inhibited their proliferation and induced apoptosis. Knocking down BMP5 in the tongue lesions of the 4NQO-induced OLK model lacking macrophages reversed the protective effect associated with macrophage depletion. CONCLUSION: The results confirmed that the macrophage-BMP5 axis is involved in the carcinogenesis of OLK.