HIF induces human embryonic stem cell markers in cancer cells

Julie Mathieu, Zhan Zhang, Wenyu Zhou, Amy J. Wang, John M. Heddleston, Claudia M.A. Pinna, Alexis Hubaud, Bradford Stadler, Michael Choi, Merav Bar, Muneesh Tewari, Alvin Liu, Robert Vessella, Robert Rostomily, Donald Born, Marshall Horwitz, Carol Ware, C. Anthony Blau, Michele A. Cleary, Jeremy N. RichHannele Ruohola-Baker

Research output: Contribution to journalArticle

345 Scopus citations

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 HIFa, 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 HIF1a-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.

Original languageEnglish (US)
Pages (from-to)4640-4652
Number of pages13
JournalCancer research
Volume71
Issue number13
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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