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

Abstract

BackgroundInadequate 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 FindingsWe 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.ConclusionsThe 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.

Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours

“…We used the survival package in R (with samples grouped by median expression) to generate Kaplan -Meier (KM) plots for the 19 FFPET arrays to test the relationship between microarray gene expression and survival. This approach is similar to those of (Chi et al, 2006;Winter et al, 2007). Receiver operating characteristic curves (ROC) for the 500-gene probe sets illustrate the sensitivity and specificity of detecting metastases within 3 years of diagnosis by gene expression, showing good performance with AUC values of 0.85 and 0.92 for up-and downregulated profiles respectively.…”

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

“…Here it was found that for both mammary epithelial and renal proximal tubule epithelial cells (22), exposure to hypoxia resulted in increased levels of JAG2 (Fig. 2C).…”

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

“…Cells can adapt to low oxygen (O 2 ) in part through activation of hypoxia-inducible factors (HIFs). HIF-1α is one of the key transcription factors in the response to hypoxia; it mediates a variety of adaptive cellular and systemic responses to hypoxia by up-regulating the expression of more than 50 different genes to assist animals in their adaptation and survival [22][23][24] . Several studies have found that myogenesis can adapt to hypoxia.…”