mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells
mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells
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DOI：
10.1158/0008-5472.can-09-1289
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
--
作者：
Matsumoto, Kazuko;Arao, Tokuzo;Nishio, Kazuto
调节癌干细胞/肿瘤起始细胞标志物CD 133/CD 133 -1在癌细胞中表达的潜在机制在很大程度上仍不清楚，尽管对该机制的了解可能会提供关于癌干细胞的重要生物学信息。在这里，我们发现在CD 133过表达的癌细胞系中，mTOR信号传导的抑制在mRNA和蛋白质水平上上调CD 133表达。这种作用被雷帕霉素的竞争者他克莫司所抵消，并且没有被常规的细胞毒性药物所改变。我们假设缺氧诱导因子-1 α（HIF-1 α），mTOR信号通路的下游分子，可能调节CD 133的表达;因此，我们研究了CD 133和HIF-1 α之间的关系。低氧条件下上调HIF-1 α表达，并在mRNA和蛋白水平上反向下调CD 133表达。类似地，HIF-1 α激活剂甲磺酸去铁胺剂量依赖性地下调CD 133表达，与缺氧条件的作用一致。最后，使用临床胃癌样本检测CD 133与HIF-1 α和HIF-1 β表达的相关性。在CD 133和HIF-1 α之间观察到强负相关（r = -0.68），但在CD 133和HIF-1 β之间没有观察到。总之，这些结果表明HIF-1 α下调CD 133表达，并表明mTOR信号转导参与癌细胞中CD 133的表达。我们的研究结果提供了一个新的洞察CD 133表达的调节机制，通过mTOR信号和HIF-1 α在癌细胞中，并可能导致洞察参与的mTOR信号和氧敏感的细胞内途径在维持干细胞在癌症干细胞。[Cancer Res 2009;69（1，8）：7 7160-4]
The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells. [Cancer Res 2009;69(1,8):7 7160-4]