Abstract

Hypoxia affects the tumor microenvironment and is considered important to metastasis progression and therapy resistance. Thus far, the majority of global analyses of tumor hypoxia responses have been limited to just a single omics level. Combining multiple omics data can broaden our understanding of tumor hypoxia. Here, we investigate the temporal change of the metabolite composition with gene expression data from literature to provide a more comprehensive insight into the system level in response to hypoxia. Nuclear magnetic resonance spectroscopy was used to perform metabolomic profiling on the MDA-MB-231 breast cancer cell line under hypoxic conditions. Multivariate statistical analysis revealed that the metabolic difference between hypoxia and normoxia was similar over 24 h, but became distinct over 48 h. Time dependent microarray data from the same cell line in the literature displayed different gene expressions under hypoxic and normoxic conditions mostly at 12 h or earlier. The direct metabolomic profiles show a large overlap with theoretical metabolic profiles deduced from previous transcriptomic studies. Consistent pathways are glycolysis/gluconeogenesis, pyruvate, purine and arginine and proline metabolism. Ten metabolic pathways revealed by metabolomics were not covered by the downstream of the known transcriptomic profiles, suggesting new metabolic phenotypes. These results confirm previous transcriptomics understanding and expand the knowledge from existing models on correlation and co-regulation between transcriptomic and metabolomics profiles, which demonstrates the power of integrated omics analysis.

Highlights

  • Previous studies have revealed the impact of tumor hypoxia on the malignant properties and propagation features of cancer [1]

  • This study aims to integrate transcriptomic and metabolomic data to increase our understanding of tumor hypoxia in breast cancer

  • (alanine, phenylalanine, glutamate, glutamine, tyrosine), which are involved in the different metabolic pathways, such as energy metabolism and carbohydrate metabolism

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Summary

Introduction

Previous studies have revealed the impact of tumor hypoxia on the malignant properties and propagation features of cancer [1]. Chan et al used patient biopsies to investigate specific biomarkers for colorectal cancer. They observed that the most characteristic markers to discriminate colorectal tumor from normal tissue are hypoxia-related metabolites [5]. Many groups have used gene expression microarrays to study breast cancer tissue at the transcriptome level. It has been shown that the hypoxic microenvironment induces the expression of more than 100 genes which alter the tumor vitality, propagation, malignant progression, metastasis and resistance to chemotherapy or radiation treatment [7,8,9,10,11]. HIFα subunit (HIF1α, 2α, or 3α) becomes stabilized and dimerized with the HIF1β subunit to form the HIF heterodimeric complex, which binds to the so-called hypoxia responsive element (HRE) within target genes to activate gene expressions that change the nature of tumor cells [14]

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