CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway

Abstract

Background Chemokine (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. Methods The 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. Results NIR1 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. Conclusion CCL18 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.

RETRACTED ARTICLE: Circ_0005320 promotes oral squamous cell carcinoma tumorigenesis by sponging microRNA-486-3p and microRNA-637

“…JAK2/STAT3 signal pathway is a classical intracellular signal transduction pathway, involved in many pathophysiological processes, including cell proliferation, differentiation, inflammation, as well as pain formation [ 17 , 31 ]. Recently, further evidence has suggested that the activation of the JAK2/STAT3 pathway plays an oncogenic role in the progression of OSCC [ 32 , 33 ]. Thus, whether circ_0005320-miR-486-3p/miR-637 axis regulated OSCC progression in a JAK2/STAT3 pathway-dependent manner was investigated.…”

CCL18 Knockdown Suppresses Cell Growth and Migration in Thyroid Cancer

“…CCL18 was reported to play a part in progression of various human tumors. For example, CCL18 promoted the development by modulating the NIR1 and JAK2/STAT3 signaling pathway in oral cancer cells [ 20 ]. In laryngeal squamous cell carcinoma, CCL18 was elevated and might be a potential biomarker [ 21 ].…”

Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway

“…Our data showed that CCL18 was the main chemokine increased in OSCC, associated to cancer cells mainly by immunohistochemical analysis. This could be explained by the important role of CCL18 in oral cancer where it promotes hyperplasia and metastasis by JAK2/ STAT3 signaling pathways (54). In fact, in a study focused on the alterations of chemokine and chemokine receptors in premalignant stages of OSCC, CCL18 was the top one gene significantly upregulated in oral leukoplakia samples in comparison with normal epithelia (55).…”