Chemokine (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.
Chemokine (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.
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趋化因子（CC 基序）配体 18 上调 Slug 表达，通过激活口腔鳞状细胞癌中雷帕霉素途径的哺乳动物靶点来促进干细胞样特征
DOI：
10.1111/cas.13289
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发表时间：
2017-08
期刊：
影响因子：
5.7
通讯作者：
Xia J
中科院分区：
文献类型：
--
作者：
Wang H;Liang X;Li M;Tao X;Tai S;Fan Z;Wang Z;Cheng B;Xia J
趋化因子（CC motif）配体18 （CCL18）参与肿瘤微环境的重塑，在肿瘤的发生、侵袭和转移中起关键作用。我们之前研究了CCL18在原发性口腔鳞状细胞癌（OSCC）组织中的过表达及其与OSCC患者晚期临床分期的关系。然而，CCL18衍生活性的潜在机制尚不清楚。本研究显示，与阴性对照相比，外源性CCL18增加了OSCC细胞的迁移和侵袭，诱导了细胞上皮-间质转化（EMT），上皮标志物E - cadherin减少，间质标志物N - cadherin增加。此外，我们检测到CCL18诱导口腔癌细胞获得癌干（样）细胞特征，但通过免疫组织化学分析也发现CCL18的表达与OSCC手术标本中的Bmi - 1呈显著正相关（P < 0.001）。与未处理的细胞相比，CCL18处理的细胞中八聚体结合转录因子4和Bmi - 1的表达显著上调，醛脱氢高+细胞和CD133+细胞的比例显著增加。当细胞持续暴露于高水平CCL18时，细胞的成球能力明显增强。此外，CCL18通过刺激哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在OSCC细胞系中上调Slug的表达。通过INK128抑制mTOR通路，或通过RNA干扰敲低Slug，可以在分子和功能水平上逆转CCL18诱导的EMT和干性反应。总之，我们的数据表明，CCL18通过激活口腔癌中的mTOR通路，上调Slug的表达，从而促进EMT和干细胞样特征。这些发现为OSCC的早期诊断和治疗提供了新的潜在靶点。
Chemokine (CC motif) ligand 18 (CCL18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL18 in primary oral squamous cell carcinoma (OSCC) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL18‐derived activity remains unidentified. This study showed exogenous CCL18 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 CCL18 induced the acquisition of cancer stem(‐like) cell characteristics in oral cancer cells, but also found 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 octamer‐binding transcription factor 4 and Bmi‐1 were significantly upregulated, and proportions of aldehyde dehydrogenasehigh+ cells and CD133+ cells were markedly increased in CCL18‐treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL18. Moreover, CCL18 upregulated Slug expression by stimulating the mammalian target of rapamycin (mTOR) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK128, or Slug knockdown by RNA interference, reversed CCL18‐induced EMT and the 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 the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.
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影响因子：
37.3
作者：
Lane D;Matte I;Laplante C;Garde-Granger P;Carignan A;Bessette P;Rancourt C;Piché A
通讯作者：
Piché A
影响因子：
--
作者：
Lin, Zeyu;Li, Wenbin;Ouyang, Nengtai
通讯作者：
Ouyang, Nengtai
影响因子：
4.8
作者：
Villarejo, Ana;Cortes-Cabrera, Alvaro;Cano, Amparo
通讯作者：
Cano, Amparo
影响因子：
7.6
作者：
Scanlon, C. S.;Van Tubergen, E. A.;D'Silva, N. J.
通讯作者：
D'Silva, N. J.
影响因子：
254.7
作者：
Torre, Lindsey A.;Bray, Freddie;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin