Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells.
Double-negative feedback loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde dehydrogenase 1-positive cancer stem cells.
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DOI：
10.1158/0008-5472.can-10-2388
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Yang X;Lin X;Zhong X;Kaur S;Li N;Liang S;Lassus H;Wang L;Katsaros D;Montone K;Zhao X;Zhang Y;Bützow R;Coukos G;Zhang L
相对罕见的醛脱氢酶1（ALDH 1）阳性的肿瘤细胞“干细胞样”亚群具有启动和维持肿瘤生长的独特能力;此外，它对化疗具有高度抗性，并与不良临床结局显著相关。开发更有效的癌症治疗方法需要靶向该细胞群。通过基因芯片分析，我们发现C.线虫lin-28同源物（LIN 28）与ALDH 1+肿瘤细胞的百分比正相关;这在一组独立的组织阵列（n=197）中得到进一步验证。功能丧失和功能获得研究均表明，LIN 28在维持ALDH 1+肿瘤细胞中起关键作用。此外，我们发现肿瘤细胞中LIN 28和let-7之间存在双重负反馈回路，let-7负调控ALDH 1+肿瘤细胞。最后，我们报告了LIN 28/let-7环调节乳腺上皮祖细胞的自我更新和分化。我们的数据提供的证据表明，癌症干细胞可能是通过“重编程样”机制产生的。LIN 28/let-7调节环的再平衡可能是靶向ALDH 1+癌症干细胞的新治疗策略。
A relatively rare aldehyde dehydrogenase 1 (ALDH1) positive “stem cell-like” subpopulation of tumor cells has the unique ability to initiate and perpetuate tumor growth; moreover it is highly resistant to chemotherapy and significantly associated with poor clinical outcomes. The development of more effective therapies for cancer requires targeting of this cell population. Using cDNA microarray analysis, we identified that the expression of the C. elegans lin-28 homolog (LIN28) was positively correlated with the percentage of ALDH1+ tumor cells; this was further validated in an independent set of tissue arrays (n=197). Both lose-of-function and gain-of-function studies demonstrated that LIN28 plays a critical role in the maintenance of ALDH1+ tumor cells. In addition, we found that there is a double negative feedback loop between LIN28 and let-7 in tumor cells, and that let-7 negatively regulates ALDH1+ tumor cells. Finally, we report that a LIN28/let-7 loop modulates self renewal and differentiation of mammary gland epithelial progenitor cells. Our data provide evidence that cancer stem cells may arise through a “reprogramming-like” mechanism. A rebalancing of the LIN28/let-7 regulatory loop could be a novel therapeutic strategy to target ALDH1+ cancer stem cells.