Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM
Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM
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DOI：
10.1002/stem.1418
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发表时间：
2013-10-01
期刊：
影响因子：
5.2
通讯作者：
Mackenzie, Ian C.
中科院分区：
文献类型：
--
作者：
Shigeishi, Hideo;Biddle, Adrian;Mackenzie, Ian C.
从头颈部肿瘤中分离出的高表达CD44的细胞具有很高的启动肿瘤的能力。这些细胞也参与了上皮向间充质转化(EMT)，我们之前已经报道，肿瘤干细胞(CSCs)以两种不同的生物学表型存在。两种表型都是CD44(高)，但一种也是ESA(高)并保持上皮特征，另一种是ESA(低)，具有间充质特征并具有迁移性。研究这些细胞中CD44调节的信号通路，我们发现CD44和RHAMM都能抑制糖原合成酶激酶3β(GSK3β)的磷酸化。我们表明，抑制磷酸化减少了“肿瘤球体”和“全克隆”克隆的形成，这两个克隆是干细胞的功能指标。抑制GSK3β还会降低干细胞标记物如Oct4、Sox2和Nanog的表达，并上调CD44(高)/ESA(高)细胞组分中分化标记物Calgrain B和Involucrin的表达。GSK3β基因敲除诱导了CSCs从EMT向上皮CSC表型的转变。这些结果表明，GSK3β在决定和维持体外CSCs的表型和行为方面发挥着核心作用，并可能参与控制体内肿瘤的生长和扩散。
Cells sorted from head and neck cancers on the basis of their high expression of CD44 have high potency for tumor initiation. These cells are also involved in epithelial to mesenchymal transition (EMT) and we have previously reported that cancer stem cells (CSCs) exist as two biologically distinct phenotypes. Both phenotypes are CD44(high) but one is also ESA(high) and maintains epithelial characteristics, the other is ESA(low), has mesenchymal characteristics and is migratory. Examining CD44-regulated signal pathways in these cells we show that CD44, and also RHAMM, act to inhibit phosphorylation of glycogen synthase kinase 3 beta (GSK3 beta). We show that inhibitory phosphorylation reduces the formation of both "tumor spheres" and "holoclone" colonies, functional indicators of stemness. GSK3 beta inhibition also reduces the expression of stem cell markers such as Oct4, Sox2, and Nanog and upregulates expression of the differentiation markers Calgranulin B and Involucrin in the CD44(high)/ESA(high) cell fraction. Transition of CSCs out of EMT and back to the epithelial CSC phenotype is induced by GSK3 beta knockdown. These results indicate that GSK3 beta plays a central role in determining and maintaining the phenotypes and behavior of CSCs in vitro and are likely to be involved in controlling the growth and spread of tumors in vivo.