Silencing of B7H4 Represses the Development of Oral Squamous Cell Carcinoma Through Promotion of M1 Macrophage Polarization
Journal of Oral and Maxillofacial Surgery(2022)
Abstract
Purpose: Tumor-associated macrophages can support oral squamous cell carcinoma (OSCC) progres-sion, and overexpression of the immunomodulator B7H4 correlates with poor prognosis of OSCC patients. We performed this study to assess the effect of B7H4 silencing on macrophage polarization and explore the potential mechanism of B7H4 during OSCC progression. Methods: Short hairpin RNA targeting B7H4 was used to knock down B7H4. The predictor variable was B7H4 expression level, and the outcome variables were SCC9 cell growth and metastasis, M1/M2 macro-phage ratio, and anti-programmed death-1 (PD-1)/STAT3 pathway-related protein levels. These were measured through real-time qPCR, Western blot analysis, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetra-zolium bromide (MTT), 5-ethynyl-2'-deoxyuridine assay, and transwell assay. In addition, a tumor xenograft mouse model was used to examine the effect of B7H4 silencing (+/-Colivelin, an activator of STAT3) on tumor growth and macrophage polarization. Results: The expression of B7H4 in OSCC cell lines was more than 2-fold compared with that in human normal oral keratinocytes via real-time qPCR and Western blot analysis. Knockdown of B7H4 repressed the proliferation, migration, and invasion of SCC9 cells, which were detected by 5-ethynyl-2'-deoxyuridine and transwell assay, as well as reduced PD-1/STAT3 pathway-related protein levels, promoted M1 macro-phage polarization, and inhibited M2 polarization. In vivo research demonstrated that B7H4 silencing also inhibited the growth of tumor xenograft and increased the M1/M2 ratio in an OSCC mouse model. Colive-lin reversed the inhibitory effects of B7H4 knockdown on OSCC progression and reversed macrophage polarization both in vitro and in vivo. Conclusions: B7H4 is upregulated during OSCC progression. Its downregulation may promote M1 macrophage polarization and inhibit M2 macrophage polarization via deactivating the PD-1/STAT3 pathway, thus restraining OSCC development.(c) 2022 American Association of Oral and Maxillofacial Surgeons
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Key words
oral squamous cell carcinoma,squamous cell carcinoma,macrophage,b7h4
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