title: HIF induces human embryonic stem cell markers in cancer cells.
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.
authors.affiliation: Department of Biochemistry, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Mathieu
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhou
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wang
authors.forename: John M
authors.initials: JM
authors.lastname: Heddleston
authors.forename: Claudia M A
authors.initials: CM
authors.lastname: Pinna
authors.forename: Alexis
authors.initials: A
authors.lastname: Hubaud
authors.forename: Bradford
authors.initials: B
authors.lastname: Stadler
authors.forename: Michael
authors.initials: M
authors.lastname: Choi
authors.forename: Merav
authors.initials: M
authors.lastname: Bar
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
authors.forename: Alvin
authors.initials: A
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.forename: Robert
authors.initials: R
authors.lastname: Rostomily
authors.forename: Donald
authors.initials: D
authors.lastname: Born
authors.forename: Marshall
authors.initials: M
authors.lastname: Horwitz
authors.forename: Carol
authors.initials: C
authors.lastname: Ware
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Blau
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Hannele
authors.initials: H
authors.lastname: Ruohola-Baker
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D051793:Hypoxia-Inducible Factor 1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; C000715187:Lin28A protein, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors