RBP4 inhibits tongue squamous cell carcinoma progression through inhibition of the PI3K/AKT signaling pathway and promotion of macrophage M1-type polarization

Tongue squamous cell carcinoma (TSCC) is a common type of oral mucosal epithelial malignancy that can severely affect patient quality of life. Therefore, novel therapeutic strategies for TSCC are needed. This study aimed to investigate the role and mechanism of action of retinol-binding protein 4 (RBP4) in TSCC progression and its effect on tumor-associated macrophages. To this end, TSCC cell lines with RBP4 over-expression and knockdown were constructed, and effects of RBP4 expression on the proliferation and inva-sive abilities of TSCC cells were verified using ex vivo experiments. Furthermore, a tumor cell-macrophage co-culture model was established to assess the effect of RBP4 on macrophage polarization. RBP4 overex-pression reduced the phosphorylation of the PI3K/Akt/mTOR pathway and inhibited tumor cell proliferation by regulating Snail levels; RBP4 inhibited TSCC cells from undergoing epithelial-mesenchymal transition. In addition, RBP4 promoted the activation of NF-κB signaling pathway, leading to macrophage polarization toward M1 type and inhibiting TSCC growth. We found for the first time that RBP4 affects the prolifera-tion and migration of TSCC cells by inhibiting the activation of the PI3K-Akt signaling pathway, and that RBP4 promotes the M1-type polarization of tumor-associated macrophages, which contributes to their on-cogenic effects.