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

Xiaoyuan Hu,Chengqin Wang,Xuan Zhang,Shengyou Ge,Yuanyong Feng,Fenggang Xiang,Fei Gao,Ning Wang

doi:10.3389/fonc.2022.812044

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.

Highlights

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity [1]
Double IHC results revealed that Chemerin and CD15+ tumor-associated neutrophils (TANs) colocalized in clinical OSCC specimens
We found that neutrophils increased the expression levels of p-JAK2, pSTAT3, Phospho-Rb, E2F1, CyclinE1, and CyclinD1 in the three OSCC cells relative to those in the control group. pJAK2, p-STAT3, Phospho-Rb, E2F1, CyclinE1, and CyclinD1 levels decreased in the Chemerin-shRNA (2#) SCC15 cells relative to those in the Scr-shRNA group

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity [1]. Treatment methods, such as chemotherapy, radiotherapy, and surgical therapy, have advanced in recent years, the 5-year survival rate of patients with OSCC has remained less than 60% [2]. Neutrophils Promote OSCC Progression have shown that the interaction between tumor cells and immune cells creates a favorable microenvironment for cancer initiation, progression, and metastasis [3, 4]. Recent studies have revealed that in addition to tumor cells, inflammation and the immune system, as indispensable participants in tumor formation, provide an attractive environment for tumor growth and metastasis. Only a few studies have been done on the specific signaling pathways and molecular mechanisms involved in the interaction between neutrophils and OSCC [10]

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