Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Base Sequence
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Cell Hypoxia
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Eukaryotic Initiation Factor-2 / metabolism
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic*
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Gene Silencing*
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Head and Neck Neoplasms / genetics*
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Head and Neck Neoplasms / metabolism
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Head and Neck Neoplasms / pathology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunoprecipitation
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Male
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Mice
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Mice, Nude
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MicroRNAs / metabolism*
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Molecular Sequence Data
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Neoplasm Transplantation
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Oligonucleotide Array Sequence Analysis
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Protein Binding
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Receptor, Fibroblast Growth Factor, Type 5 / genetics
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Receptor, Fibroblast Growth Factor, Type 5 / metabolism
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Reproducibility of Results
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Response Elements
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Stress, Physiological / genetics*
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic
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Transduction, Genetic
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Up-Regulation
Substances
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Eukaryotic Initiation Factor-2
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FGFRL1 protein, human
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HIF1A protein, human
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Homeodomain Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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MIRN210 microRNA, human
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MicroRNAs
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Receptor, Fibroblast Growth Factor, Type 5
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Transcription Factors
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homeobox A1 protein
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homeobox protein HOXA9