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PMID: 19782034 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation.

Molecular cell ·Vol. 35 ·No. 6 ·2009-09-24 ·Pages 856-67

Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT, Giaccia AJ

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.

MeSH Terms
Animals Base Sequence Cell Hypoxia Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic/genetics,metabolism,pathology Eukaryotic Initiation Factor-2/metabolism Gene Expression Profiling/methods Gene Expression Regulation, Neoplastic Gene Silencing Head and Neck Neoplasms/genetics,metabolism,pathology Homeodomain Proteins/genetics,metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Immunoprecipitation Male Mice Mice, Nude MicroRNAs/metabolism Molecular Sequence Data Neoplasm Transplantation Oligonucleotide Array Sequence Analysis Pancreatic Neoplasms/genetics,metabolism,pathology Protein Binding Receptor, Fibroblast Growth Factor, Type 5/genetics,metabolism Reproducibility of Results Response Elements Stress, Physiological/genetics Time Factors Transcription Factors/genetics,metabolism Transcription, Genetic Transduction, Genetic Up-Regulation
Chemicals
Eukaryotic Initiation Factor-2 FGFRL1 protein, human HIF1A protein, human Homeodomain Proteins Hypoxia-Inducible Factor 1, alpha Subunit MIRN210 microRNA, human MicroRNAs Receptor, Fibroblast Growth Factor, Type 5 Transcription Factors homeobox A1 protein homeobox protein HOXA9
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Huang Xin
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94025, USA.
Ding Lianghao
Bennewith Kevin L
Tong Ricky T
Welford Scott M
Ang K Kian
Story Michael
Le Quynh-Thu
Giaccia Amato J
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2009.09.006
Published
2009-09-24
Pages
856-67
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2782615
Subset
IM
Grants
NCI NIH HHS · P01 CA067166 · United States
NCI NIH HHS · P01-CA67166 · United States
NCI NIH HHS · 1R01-CA118582 · United States
NCI NIH HHS · R01 CA118582 · United States
NCI NIH HHS · P01 CA067166-13 · United States
NCI NIH HHS · P01-CA06294 · United States
Corrections
CommentIn
PMID: 19782023
External Links
PubMed source DOI: 10.1016/j.molcel.2009.09.006 PMC Full Text View journal details
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