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Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers

BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-de...

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Autores principales: Chi, Jen-Tsan, Wang, Zhen, Nuyten, Dimitry S. A, Rodriguez, Edwin H, Schaner, Marci E, Salim, Ali, Wang, Yun, Kristensen, Gunnar B, Helland, Åslaug, Børresen-Dale, Anne-Lise, Giaccia, Amato, Longaker, Michael T, Hastie, Trevor, Yang, George P, van de Vijver, Marc J, Brown, Patrick O
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1334226/
https://www.ncbi.nlm.nih.gov/pubmed/16417408
http://dx.doi.org/10.1371/journal.pmed.0030047
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author Chi, Jen-Tsan
Wang, Zhen
Nuyten, Dimitry S. A
Rodriguez, Edwin H
Schaner, Marci E
Salim, Ali
Wang, Yun
Kristensen, Gunnar B
Helland, Åslaug
Børresen-Dale, Anne-Lise
Giaccia, Amato
Longaker, Michael T
Hastie, Trevor
Yang, George P
van de Vijver, Marc J
Brown, Patrick O
author_facet Chi, Jen-Tsan
Wang, Zhen
Nuyten, Dimitry S. A
Rodriguez, Edwin H
Schaner, Marci E
Salim, Ali
Wang, Yun
Kristensen, Gunnar B
Helland, Åslaug
Børresen-Dale, Anne-Lise
Giaccia, Amato
Longaker, Michael T
Hastie, Trevor
Yang, George P
van de Vijver, Marc J
Brown, Patrick O
author_sort Chi, Jen-Tsan
collection PubMed
description BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1α protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1α RNA in renal cells, and it could be diminished by reducing HIF-1α expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer.
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spelling pubmed-13342262006-03-30 Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers Chi, Jen-Tsan Wang, Zhen Nuyten, Dimitry S. A Rodriguez, Edwin H Schaner, Marci E Salim, Ali Wang, Yun Kristensen, Gunnar B Helland, Åslaug Børresen-Dale, Anne-Lise Giaccia, Amato Longaker, Michael T Hastie, Trevor Yang, George P van de Vijver, Marc J Brown, Patrick O PLoS Med Research Article BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1α protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1α RNA in renal cells, and it could be diminished by reducing HIF-1α expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer. Public Library of Science 2006-03 2006-01-24 /pmc/articles/PMC1334226/ /pubmed/16417408 http://dx.doi.org/10.1371/journal.pmed.0030047 Text en Copyright: © 2006 Chi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chi, Jen-Tsan
Wang, Zhen
Nuyten, Dimitry S. A
Rodriguez, Edwin H
Schaner, Marci E
Salim, Ali
Wang, Yun
Kristensen, Gunnar B
Helland, Åslaug
Børresen-Dale, Anne-Lise
Giaccia, Amato
Longaker, Michael T
Hastie, Trevor
Yang, George P
van de Vijver, Marc J
Brown, Patrick O
Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title_full Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title_fullStr Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title_full_unstemmed Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title_short Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers
title_sort gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1334226/
https://www.ncbi.nlm.nih.gov/pubmed/16417408
http://dx.doi.org/10.1371/journal.pmed.0030047
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