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Tumor-derived CCL20 activates tumor-associated neutrophils, predicting good prognosis in endometrial cancer
Linyan Zhu1,2, Wenwu Luo1, Siyu Li2
1Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background:
Endometrial cancer (EC) is the sixth most common cancer in women. A rising age-standardized incidence rate of EC has been observed globally. Tumor-associated neutrophils (TANs) have been demonstrated to be a "double-edged sword" in human cancers. We aimed to study the role of CCL20 and neutrophil infiltration in human EC in the study.
Methods:
Differential expression genes (DEGs) associated with chemokines in EC compared with normal samples were analyzed based on The Cancer Genome Atlas (TCGA)-Uterine Corpus Endometrial Carcinoma (UCEC) database, and DEGs associated with neutrophil infiltration were screened out as candidate genes. Through clinical samples, we verified the expression of CCL20 in EC tissues. Gene set enrichment analysis (GSEA) was performed. Through a supernatant co-culture system, flow cytometry and immunofluorescence, we studied the effect of CCL20 on neutrophils. The correlation of CCL20 and neutrophil infiltration with clinicopathological parameters and survival rates in EC patients was analyzed based on TCGA-UCEC database. It was validated through Gene Expression Omnibus (GEO) database and local samples.
Results:
CCL20 was screened out to be highly expressed and associated with neutrophil infiltration in EC. CCL20 was associated with immune-related signaling pathways including NOD-like receptor, TNF, NF-kappa B and IL-17. Through a supernatant co-culture system, we examined that EC cell-derived CCL20 enhanced cell viability and programmed death-ligand 1 (PD-L1) expression in neutrophils. Data from TCGA database showed that CCL20 level was negatively correlated with International Federation of Gynecology and Obstetrics (FIGO)-stage and Histopathological Grade, and associated with good prognosis in EC patients. Local tissue study demonstrated CCL20 was overexpressed in EC tissues and the expression level of CCL20 was negatively correlated with FIGO-stage in EC patients.
Conclusions:
CCL20 is an important biomarker in human EC, which is highly expressed and is strongly correlated with neutrophil infiltration in EC. Moreover, high level of CCL20 and neutrophil infiltration are associated with favorable prognosis in patients with EC. Our findings suggest that CCL20 could be potentially used for prognostic prediction and treatment in human EC.
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