The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers
The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers
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DOI：
10.1158/0008-5472.can-10-2350
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Yu, Yau-Hua
中科院分区：
文献类型：
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作者：
Lo, Jeng-Fan;Yu, Cheng-Chia;Yu, Yau-Hua
癌症起始细胞（CIC）包括肿瘤中被认为负责肿瘤生长的罕见细胞亚群。从头颈部鳞状细胞癌（HNSCC）中鉴定的CIC（称为头颈部癌起始细胞（HN-CIC））开始，我们确定促炎介质S100 A4作为HN-CIC的候选干细胞维持分子，该促炎介质S100 A4也已知是上皮-间充质转化的诱导剂。在体外和体内，HN-CIC中的S100 A4敲低降低了它们的自我更新能力以及它们的干性和致瘤性。相反，S100 A4在HNSCC细胞中的过表达增强了它们的干细胞特性。机制研究表明，HNSCC细胞中内源性S100 A4水平的减弱引起Notch 2和PI 3 K（磷酸肌醇3-激酶）/pAKT的下调，沿着PTEN的上调，这与生物学发现一致。HNSCC临床标本的免疫组化分析显示，S100 A4表达与临床分级、干性标志物和较差的患者生存率呈正相关。总之，我们的研究结果揭示了S100 A4信号通路在维持HN-CIC的干性和致瘤性方面的关键作用。此外，我们的研究结果表明，靶向S100 A4信号可能通过消除HN-CIC为HNSCC治疗提供新的靶向策略。Cancer Res; 71（5）; 1912-23. (c)2010年AACR。
Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemness-maintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs. Cancer Res; 71(5); 1912-23. (c) 2010 AACR.