“…7 i, j). Since our previous studies demonstrated that Dusp1 gene deficiency can promote the growth of OSCC and enhance M2 macrophage polarization [ 52 ], we suggest that CCR7 promotion of M2 polarization is dependent on Dusp1 loss. Fig.…”
Section: Resultsmentioning
confidence: 80%
“…Dusp1 can negatively regulate the immune response by directly dephosphorylating p38 and JNK and may also compete with upstream mapkks and downstream substrates to participate in the regulation of MAPKs by binding with p38 or JNK [ 84 ]. Our previous research has shown that Dusp1 gene deficiency can promote the polarization of M2 macrophages and the growth of OSCC in mice [ 85 ]. According to previous results and the results of this study, in which CCR7 knockout inhibited M2 macrophage polarization and promoted Dusp1 expression in M2 macrophages, we can conclude that CCR7 promotes OSCC growth via Dusp1 -regulated M2 macrophage polarization.…”
Background
Studies have shown that CCR7, an important inflammatory factor, can promote the proliferation and metastasis of oral squamous cell carcinoma (OSCC), but its role in the tumor microenvironment (TME) remains unclear. This paper explores the role of CCR7 in the TME of OSCC.
Methods
In this work, we constructed CCR7 gene knockout mice and OSCC mouse models. Single-cell RNA sequencing (scRNA-seq) and bioinformatics were used to analyze the differences in the OSCC microenvironment between three CCR7 gene knockout mice (KO) and three wild-type mice (WT). Immunohistochemistry, immunofluorescence staining, and flow cytometry were used to analyze the expression of key genes in significantly different cell types between the KO and WT groups. An in vitro experiment was used to verify the effect of CCR7 on M2 macrophage polarization.
Results
In the mouse OSCC models, the tumor growth rate in the KO group was significantly lower than that in the WT group. Eight main cell types (including tumor cells, fibroblasts, macrophages, granulocytes, T cells, endothelial cells, monocytes, and B cells) were identified by Seurat analysis. The scRNA-seq results showed that the proportion of tumor cells was lower, but the proportion of inflammatory cells was significantly higher in the KO group than in the WT group. CellPhoneDB analysis results indicated a strong interaction relationship between tumor cells and macrophages, T cells, fibroblasts, and endothelial cells. Functional enrichment results indicated that the expression level of the Dusp1 gene in the KO group was generally higher than that in the WT group in various cell types. Macrophage subclustering results indicated that the proportion of M2 macrophages in the KO group was lower than that in the WT group. In vitro experimental results showed that CCR7 can promote M2 macrophage polarization, thus promoting the proliferation, invasion and migration of OSCC cells.
Conclusions
CCR7 gene knockout can significantly inhibit the growth of mouse oral squamous cell carcinoma by promoting the polarization of M2 macrophages.
“…7 i, j). Since our previous studies demonstrated that Dusp1 gene deficiency can promote the growth of OSCC and enhance M2 macrophage polarization [ 52 ], we suggest that CCR7 promotion of M2 polarization is dependent on Dusp1 loss. Fig.…”
Section: Resultsmentioning
confidence: 80%
“…Dusp1 can negatively regulate the immune response by directly dephosphorylating p38 and JNK and may also compete with upstream mapkks and downstream substrates to participate in the regulation of MAPKs by binding with p38 or JNK [ 84 ]. Our previous research has shown that Dusp1 gene deficiency can promote the polarization of M2 macrophages and the growth of OSCC in mice [ 85 ]. According to previous results and the results of this study, in which CCR7 knockout inhibited M2 macrophage polarization and promoted Dusp1 expression in M2 macrophages, we can conclude that CCR7 promotes OSCC growth via Dusp1 -regulated M2 macrophage polarization.…”
Background
Studies have shown that CCR7, an important inflammatory factor, can promote the proliferation and metastasis of oral squamous cell carcinoma (OSCC), but its role in the tumor microenvironment (TME) remains unclear. This paper explores the role of CCR7 in the TME of OSCC.
Methods
In this work, we constructed CCR7 gene knockout mice and OSCC mouse models. Single-cell RNA sequencing (scRNA-seq) and bioinformatics were used to analyze the differences in the OSCC microenvironment between three CCR7 gene knockout mice (KO) and three wild-type mice (WT). Immunohistochemistry, immunofluorescence staining, and flow cytometry were used to analyze the expression of key genes in significantly different cell types between the KO and WT groups. An in vitro experiment was used to verify the effect of CCR7 on M2 macrophage polarization.
Results
In the mouse OSCC models, the tumor growth rate in the KO group was significantly lower than that in the WT group. Eight main cell types (including tumor cells, fibroblasts, macrophages, granulocytes, T cells, endothelial cells, monocytes, and B cells) were identified by Seurat analysis. The scRNA-seq results showed that the proportion of tumor cells was lower, but the proportion of inflammatory cells was significantly higher in the KO group than in the WT group. CellPhoneDB analysis results indicated a strong interaction relationship between tumor cells and macrophages, T cells, fibroblasts, and endothelial cells. Functional enrichment results indicated that the expression level of the Dusp1 gene in the KO group was generally higher than that in the WT group in various cell types. Macrophage subclustering results indicated that the proportion of M2 macrophages in the KO group was lower than that in the WT group. In vitro experimental results showed that CCR7 can promote M2 macrophage polarization, thus promoting the proliferation, invasion and migration of OSCC cells.
Conclusions
CCR7 gene knockout can significantly inhibit the growth of mouse oral squamous cell carcinoma by promoting the polarization of M2 macrophages.
“…In a hepatocellular carcinoma model, miR-101-reduced DUSP1 macrophages polarized toward M2 were found to have a prolonged activation of ERK1/2, p38, and JNK-stress-activated protein kinase, decreased TGF-β and CD206 expression, and an increased production of TNF-α and IL-6 compared to wild-type cells slowing macrophage-driven hepatocellular carcinoma (Figure 4) [157]. The increased polarization of macrophages toward M2 was also found with a DUSP1 deficiency in an oral cancer mice model, implying that DUSP1 deficiency enhances tumor-associated inflammation [45,158]. Elevated levels of cytokines and chemokines IL-1β, VEGF, CXCL1, CXCL2, C-C motif ligand 2 (CCL2), and CCR5 receptor, and increased leukocyte counts (both histologically and by Ptprc gene expression in mice) were observed (Figure 4) [110].…”
The regulation of protein kinases by dephosphorylation is a key mechanism that defines the activity of immune cells. A balanced process of the phosphorylation/dephosphorylation of key protein kinases by dual-specificity phosphatases is required for the realization of the antitumor immune response. The family of dual-specificity phosphatases is represented by several isoforms found in both resting and activated macrophages. The main substrate of dual-specificity phosphatases are three components of mitogen-activated kinase signaling cascades: the extracellular signal-regulated kinase ERK1/2, p38, and Janus kinase family. The results of the study of model tumor-associated macrophages supported the assumption of the crucial role of dual-specificity phosphatases in the formation and determination of the outcome of the immune response against tumor cells through the selective suppression of mitogen-activated kinase signaling cascades. Since mitogen-activated kinases mostly activate the production of pro-inflammatory mediators and the antitumor function of macrophages, the excess activity of dual-specificity phosphatases suppresses the ability of tumor-associated macrophages to activate the antitumor immune response. Nowadays, the fundamental research in tumor immunology is focused on the search for novel molecular targets to activate the antitumor immune response. However, to date, dual-specificity phosphatases received limited discussion as key targets of the immune system to activate the antitumor immune response. This review discusses the importance of dual-specificity phosphatases as key regulators of the tumor-associated macrophage function.
“…Over the past years, as people's habits, diets and working environment, the incidence of CC has been on the rise year by year, becoming a more common malignant tumor of the reproductive system (8). Patients with CC were mainly present with clinical symptoms, such as thin, watery fluid, leucorrhoea, irregular vaginal bleeding, anaemia and painful sexual intercourse, which seriously affect closely related to the severity of CC disease (17).…”
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