Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation.
Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth.
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94025, USA.
Xin
X
Huang
Lianghao
L
Ding
Kevin L
KL
Bennewith
Ricky T
RT
Tong
Scott M
SM
Welford
K Kian
KK
Ang
Michael
M
Story
Quynh-Thu
QT
Le
Amato J
AJ
Giaccia
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051500:Receptor, Fibroblast Growth Factor, Type 5 / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020218:Response Elements; D013312:Stress, Physiological / Q000235:genetics*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D015854:Up-Regulation; D000099261:Homeobox A1 Protein
D015852:Eukaryotic Initiation Factor-2; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D051500:Receptor, Fibroblast Growth Factor, Type 5; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C417531:FGFRL1 protein, human; C497442:HIF1A protein, human; C543800:MIRN210 microRNA, human; C097899:homeobox protein HOXA9