Neutrophils Promote Tumor Progression in Oral Squamous Cell Carcinoma by Regulating EMT and JAK2/STAT3 Signaling Through Chemerin

Abstract

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. In the tumor microenvironment, tumor-associated neutrophils (TANs) can promote tumor growth, invasion, and metastasis. The aim of our study was to explore the relationship between neutrophils infiltration and Chemerin expression in tumor cells, as well as their relationship with the clinicopathological parameters and clinical prognosis of 74 cases of OSCC. We also explored the role of the interaction between neutrophils and Chemerin in the functions of OSCC cells (Cal27, SCC9, and SCC15) in vitro. Our results showed that in OSCC, Chemerin over-expression may increase neutrophils infiltration in tumor tissues. Chemerin over-expression and neutrophils infiltration were the prognostic factors of poor clinical outcomes. Furthermore, we discovered that neutrophils promoted OSCC migration, invasion, and proliferation and EMT through Chemerin. Neutrophils activated JAK2/STAT3 signaling through Chemerin and then up-regulated its downstream signaling target genes, such as Phospho-Rb, E2F1, CyclinE1, and CyclinD1. Taken together, our results revealed that neutrophils and Chemerin are potentially involved in OSCC progression and metastasis. Neutrophils may promote the JAK2/STAT3 signaling pathway and EMT in OSCC cells through Chemerin.

Targeting Tumor Microenvironment Akt Signaling Represents a Potential Therapeutic Strategy for Aggressive Thyroid Cancer

“…We next examined the potential signaling pathways that might mediate the effects of tumor stromal cells on CSCs. According to the findings in recent studies, there are several signaling pathways, including JAK/STAT [ 59 , 60 , 61 , 62 , 63 ], PI3K/Akt [ 64 , 65 , 66 , 67 , 68 , 69 , 70 ], NF-kB [ 71 , 72 , 73 , 74 , 75 , 76 ], and TGF-β signaling [ 77 , 78 , 79 , 80 , 81 , 82 , 83 ], that could possibly be mediating the stromal cell functioning in PTC, as these signaling pathways have been found to be involved in the effects of stromal cells on tumor cells [ 59 , 60 , 61 , 62 , 63 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ]. To unveil the potentially engaged signaling pathways, we examined the expression of specific molecules that indicate different signaling pathway activities with Western blotting analyses.…”

Neutrophils: Musketeers against immunotherapy

“…Consistently, TGF-β pathways stimulate both EMT and the neutrophil pro-tumor phenotype (N2), which is likewise associated with therapy resistance ( 101 ). Emerging evidence suggests that neutrophils stimulate tumor progression through inducing EMT ( 60 , 109 , 110 ). It is well documented that both the neutrophils and EMT play a critical role in tumor progression and immunotherapy resistance ( 105 , 111 ).…”

Roles of tumor-associated neutrophils in tumor metastasis and its clinical applications

“…Antibodies that neutralize IL-17a reduce tumor progression in gastric cancer (GC) cells ( Li et al, 2019 ). Moreover, in an oral squamous cell carcinoma (OSCC) model, TANs also promoted EMT in OSCC cells by activating JAK2/STAT3 signaling ( Hu et al, 2022 ).…”