Abstract：
:Low oxygen levels have been 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 been 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 an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable 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. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions.
journal_name
Cancer Resjournal_title
Cancer researchauthors
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 Hdoi
10.1158/0008-5472.CAN-10-3320subject
Has Abstractpub_date
2011-07-01 00:00:00pages
4640-52issue
13eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-3320journal_volume
71pub_type
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