CCL18 promotes the metastasis of squamous cell carcinoma of the head and neck through MTDH‐NF‐κB signalling pathway

Yuexiang Qin,Xiyu Chen,Changhan Chen,Juncheng Wang,Yong Liu,Haolei Tan,Leiming Pi,Xin Zhang,Guo Li,Ming Wei,Zhexuan Li,Zhifeng Liu,Donghai Huang,Li She,Gangcai Zhu

doi:10.1111/jcmm.14168

Abstract

Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C‐C motif) ligand 18 (CCL18), derived from tumour‐associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial‐mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18‐induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF‐κB signalling pathway was involved in the MTDH knock‐down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment‐naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH‐NF‐κB signalling pathway.

Highlights

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most aggressive malignancy worldwide.[1]
In the pre‐ sent study, serum CCL18 levels were found to be significantly high in patients with SCCHN compared to precancerous lesions of SCCHN patients and healthy controls, and its levels correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients
Our ELISA results revealed that serum levels of CCL18 were significantly high in patients with SCCHN compared to the precancerous lesions of SCCHN patients and healthy con‐ trols

Summary

| BACKGROUND

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most aggressive malignancy worldwide.[1]. Metadherin (MTDH), known as astrocyte‐elevated gene‐1 and LYsine‐RIch CEACAM1 co‐isolated protein, was initially cloned as HIV‐1 and tumour necrosis factor α‐inducible gene in primary human foetal astrocytes.[26,27,28,29] MTDH is a downstream target of Ha‐ras and c‐myc and helps in mediating their biological effects, suggesting a potential role of MTDH in tumour initiation and progression.[30,31] Overexpression of MTDH in normal immor‐ tal cloned rat embryo fibroblasts was found to induce anchorage‐ independent growth in soft agar and enhance invasion in nude mice.[32] Several studies have demonstrated that elevated MTDH expression is closely related to poor prognosis of various types of cancers, including breast cancer,[33] oesophageal squamous cell carcinoma,[34] gastric cancer,[35] hepatocellular carcinoma[36] and non‐small cell lung cancer.[37] MTDH is a potential prognostic biomarker for human malignancies. It is unknown whether the NF‐κB signalling pathway is involved in the regulation of metastasis by CCL18 in SCCHN cells

| MATERIALS AND METHODS

Findings

| DISCUSSION