CCL18 upregulates Slug expression to promote stem-cell like features by activating mTOR pathway in oral squamous cell carcinoma

Summary

Chemokine (CC motif) ligand 18 (CCL18) is involved in the remodeling of tumor microenvironment and have critical roles in oncogenesis, invasiveness and metastasis. We previously investigated that CCL18 was overexpressed in primary oral squamous cell carcinoma (OSCC) tissues and associated with advanced clinical stage of OSCC patients. However, the underlying mechanisms of this CCL18-derived activity remains unidentified. This study showed exogenous CCL18 increased cell migration, invasion and induced cell epithelial-to-mesenchymal transition (EMT), displaying that E-cadherin, an epithelial marker, decreased and N-cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected CCL18 induced the acquisition of cancer stem(-like) cells (CSCs) characteristics in oral cancer cells, but also demonstrated a significantly positive correlation between the expression of CCL18 and Bmi-1 (P<0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of OCT4 and Bmi-1 were significantly upregulated, and proportions of ALDH^high+ cells and CD133⁺cells were markedly increased in CCL18-treated cells compared to untreated cells. The ability of sphere formation was observably enhanced when cells were continued to expose in high level of CCL18. Moreover, CCL18 upregulated Slug expression via stimulating mTOR signaling pathway in OSCC cell lines. Inhibition of mTOR pathway by INK128 or Slug knockdown by RNA interference, reversed CCL18-induced EMT and stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem-cell like features by activating mTOR pathway in oral cancer, which provide new potential targets for early diagnosis and treatment of OSCC.

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