Open AccessChemokine ( CC motif) ligand 18 upregulates Slug expression to promote stem‐cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma
Author(s) -
Wang Hongfei,
Liang Xueyi,
Li Mianxiang,
Tao Xiaoan,
Tai Shanshan,
Fan Zhaona,
Wang Zhi,
Cheng Bin,
Xia Juan
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13289
Subject(s) - epithelial–mesenchymal transition , cancer research , slug , chemistry , cancer stem cell , gene knockdown , downregulation and upregulation , pi3k/akt/mtor pathway , cell growth , stem cell , carcinogenesis , cell , chemokine , cell migration , mesenchymal stem cell , biology , microbiology and biotechnology , signal transduction , receptor , cancer , apoptosis , biochemistry , genetics , gene
Chemokine ( CC motif) ligand 18 ( CCL 18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL 18 in primary oral squamous cell carcinoma ( OSCC ) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL 18‐derived activity remains unidentified. This study showed exogenous CCL 18 increased cell migration and invasion and induced cell epithelial–mesenchymal transition ( EMT ), and that E‐cadherin, an epithelial marker, decreased and N‐cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected that CCL 18 induced the acquisition of cancer stem(‐like) cell characteristics in oral cancer cells, but also found a significantly positive correlation between the expression of CCL 18 and Bmi‐1 ( P < 0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of octamer‐binding transcription factor 4 and Bmi‐1 were significantly upregulated, and proportions of aldehyde dehydrogenase high+ cells and CD 133 + cells were markedly increased in CCL 18‐treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL 18. Moreover, CCL 18 upregulated Slug expression by stimulating the mammalian target of rapamycin ( mTOR ) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK 128, or Slug knockdown by RNA interference, reversed CCL 18‐induced EMT and the stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL 18 upregulated Slug expression to promote EMT and stem cell‐like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.