Silencing THBS1 in M2 Macrophages Exerts an Inhibitory Effect on Tongue Squamous Cell Carcinoma by Suppressing TGF-β Pathway.

Abstract

Tongue squamous cell carcinoma (TSCC) is a common oral and maxillofacial malignancy. Thrombospondin-1 (THBS1), acting in the extracellular matrix, impacts cell migration and proliferation, significantly contributing to tumor development. We aim to investigate the role of THBS1 in TSCC. Differentially expressed genes (DEGs) were screened by sequencing using macrophages obtained from TSCC patients. Hub genes were identified from protein-protein interaction (PPI) networks. Proliferation, migration, and invasion were assessed to determine the role of THBS1 in TSCC cells. Hematoxylin-eosin staining and immunohistochemistry were utilized to explore the effect of THBS1 on xenograft models. Western blot was used to determine protein expression related to M2 macrophages, angiogenesis, epithelial-mesenchymal transition (EMT), and key pathways. MMP2, THBS1, EDN1, and PERP were hub genes of TSCC, which were upregulated in M2 macrophages. Silencing THBS1 suppressed the polarization of M2 macrophages, proliferation, migration, and invasion of TSCC cells. THBS1 silencing in M2 macrophages suppressed tumor growth in mice. THBS1 silencing in M2 macrophages inhibited angiogenesis and EMT in TSCC. TGF-β pathway was a potential downstream pathway by comprehensive bioinformatics analysis. Silencing THBS1 decreased the expression of TGF-β pathway proteins in TSCC. The activation of the TGF-β pathway induced by SRI-011381 counteracted the inhibitory impacts of THBS1 silencing on M2 macrophage polarization, proliferation, migration, and invasion of TSCC cells. THBS1 silencing inhibits the polarization of M2 macrophages to hinder TSCC progression via suppressing the TGF-β pathway.