HIF induces human embryonic stem cell markers in cancer cells.
HIF induces human embryonic stem cell markers in cancer cells.
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DOI：
10.1158/0008-5472.can-10-3320
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Ruohola-Baker H
中科院分区：
文献类型：
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作者：
Mathieu J;Zhang Z;Zhou W;Wang AJ;Heddleston JM;Pinna CM;Hubaud A;Stadler B;Choi M;Bar M;Tewari M;Liu A;Vessella R;Rostomily R;Born D;Horwitz M;Ware C;Blau CA;Cleary MA;Rich JN;Ruohola-Baker H
低氧水平已被证明可以促进许多干细胞的自我更新。在肿瘤中，缺氧与侵袭性病程和不良临床结果相关。此外，许多侵袭性肿瘤显示出人类胚胎干细胞（hESC）特征的基因表达特征。我们现在测试了缺氧是否可能与侵袭性肿瘤中观察到的hESC特征有关。我们发现，缺氧可以通过缺氧诱导因子（HIF）在11种肿瘤细胞系（前列腺、脑、肾、宫颈、肺、结肠、肝和乳腺肿瘤）中诱导一种类似hesc的转录程序，包括iPSC诱导剂OCT4、NANOG、SOX2、KLF4、cMYC和miRNA-302。此外，不可降解形式的HIFα与传统的iPSC诱导剂结合，可以高效地产生具有高致瘤能力的A549 iPSC样菌落。为了检验iPSC诱导剂与原发性肿瘤中HIF表达之间的潜在相关性，我们分析了原发性前列腺肿瘤，发现NANOG-、OCT4-和hif1 α-阳性区域之间存在显著相关性。此外，NANOG和OCT4表达与前列腺肿瘤Gleason评分升高呈正相关。在原发性胶质瘤来源的CD133阴性细胞中，神经球和hESC标记物在缺氧条件下被诱导，而在常氧条件下则没有。综上所述，这些发现表明HIF靶点可能是病理状态下干细胞动态状态的关键诱导剂。
Low oxygen levels have shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia inducible factor (HIF), can induce a hESC-like transcriptional program, including the iPSC inducers, OCT4, NANOG, SOX2, KLF4, cMYC and miRNA-302 in eleven cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver and breast tumors). Further, non-degradable forms of HIFα, combined with the traditional iPSC inducers are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4- and HIF1α-positive regions. Further, NANOG and OCT4 expression positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells neurospheres and hESC markers were induced in hypoxia but not in normoxia. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathological conditions.