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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301618 | GEO | 2026/01/11

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAb) and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift towards an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T-cell proliferation and IFNγ secretion. Indeed, M1-like and M2-like macrophage differentiation involves complex signaling pathways leading to specific gene expression profiles. Typically, stimuli from the TME induce pathways including JAK/STATs, MAPK, PI3K/AKT, NOTCH and NF-κB influencing TAMs polarization. We investigated the signaling pathways activated in monocytes and M-CSF-induced M2-like macrophages upon BTN2A1 engagement using anti-BTN2A mAb5. After 30 min of treatment, we observed phosphorylation of MAPKs (i.e. ERK1/2, P38 and JNK) in CD14+ monocytes and in M2-like macrophages, unlike isotype control-treated cells. In contrast, the PI3K/AKT, JAK/STAT, and NF-kB pathways were not consistently activated after 30 min of anti-BTN2A mAb5 treatment. Since BTN2A1 lacks intrinsic kinase activity, we explored whether BTN2A1 could form complexes with molecular partners in M2-like macrophages that provide kinase activity. We prepared lysates from M2-like macrophages treated with mAb5 or with its isotype control for 30 min and performed immunoprecipitation (IP) using another anti-BTN2A mAb followed by western blotting with anti-phosphoTyrosine (pTyr). A 70 kDa was co-immunoprecipitated with BTN2A1 and revealed by the anti-pTyr in lysates from anti-BTN2A mAb5-treated M2-like macrophages. To identify which Tyrosine kinase is enriched in anti-BTN2A mAb5-treated M2-like macrophages, we performed LC-MS/MS on anti-pTyr immunoprecipitates from treated cells. Several tyrosine kinases, including P38α/δ and JNK, were enriched. Notably, SYK was also identified and matched the 72kDa molecular weight of the pTyr band co-immunoprecipitated with BTN2A1.

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

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