Abstract
BackgroundChemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors. Our previous work has shown that CCL18 promotes hyperplasia and invasiveness of oral cancer cells; however, the cognate receptors of CCL18 involved in the pathogenesis of oral squamous cell carcinoma (OSCC) have not yet been identified. This study aimed to investigate the molecular mechanisms which underlie promotive effects of CCL18 on OSCC progression by binding to functional receptors.MethodsThe expression of CCL18 receptor-NIR1 in OSCC was determined by conducting western blot, immunofluorescence, and immunocytochemistry assays. Chi square test was applied to analyze the relationship between expression levels of NIR1 and clinicopathological variables. Recombinant CCL18 (rCCL18), receptor siRNA and JAK specific inhibitor (AG490) were used in experiments investigating the effects of the CCL18-NIR1 axis on growth of cancer cells (i.e., proliferation, and metastasis), epithelial-mesenchymal transition (EMT) and the activation of the JAK2/STAT3 signaling pathway.ResultsNIR1 as functional receptor of CCL18 in OSCC, was found to be significantly upregulated in OSCC and positively related to the TNM stage of OSCC patients. rCCL18 induced the phenotypical alterations in oral cancer cells including cell growth, metastasis and EMT. The JAK2/STAT3 signaling pathway was confirmed to be a downstream pathway mediating the effects of CCL18 in OSCC. AG490 and knockdown of NIR1 could block the effects of rCCL18-induced OSCC.ConclusionCCL18 can promote the progression of OSCC by binding NIR1, and the CCL18-NIR1 axis can activate JAK2/STAT3 signaling pathway. The identification of the mechanisms underlying CCL18-mediated promotion of OSCC progression could highlight potential therapeutic targets for treating oral cancer.
Highlights
Chemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors
N-terminal domain interacting receptor 1 (NIR1) expression in oral squamous cell carcinoma (OSCC) and its clinical significance NIR1 is the most common receptor of Chemokine ligand 18 (CCL18), and their potent combination has been verified in breast cancer [18]
We examined the expression levels of NIR1 in 3 OSCC cell lines (HSC6, CAL27 and SCC9) and in normal human oral epithelial keratinocytes (HOK). qRT-PCR, western blot, and immunofluorescence (IF) assays verified that NIR1 was highly expressed in all OSCC cells as compared to HOK cells (Fig. 1c-e, Fig. S1)
Summary
Chemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors. This study aimed to investigate the molecular mechanisms which underlie promotive effects of CCL18 on OSCC progression by binding to functional receptors. Chemokines play important mechanistic roles in tumor development and have been shown to promote metastasis in OSCC by facilitating the proliferation, survival, and migration of cancer cells, as well as by alteration of the tumor microenvironment [3,4,5]. Our previous work have shown that the dysregulation of chemokine (C-C motif) ligand 18 (CCL18) is involved in the development of OSCC by promoting the growth and invasion of cancer cells [6]. NIR1 can bind to CCL18, which further stimulates calcium signaling, and elicits a cancer-promoting function in various malignancies (e.g., breast cancer, non-small cell lung cancer and ovarian cancer) [9,10,11]. Whether CCR8 and CCR6 play significantly impact mechanistic roles in OSCC is yet not understood
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