Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia

Frida Danielsson, Erik Fasterius, Devin Sullivan, Linnea Hases, Kemal Sanli, Cheng Zhang, Adil Mardinoglu, Cristina Al-Khalili, Mikael Huss, Mathias Uhlén, Cecilia Williams, Emma Lundberg

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Abstract

In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.
Original languageEnglish
JournalOncoTarget
Volume9
Issue number28
Pages (from-to)19730-19744
ISSN1949-2553
DOIs
Publication statusPublished - 2018

Keywords

  • Hypoxia
  • Transcriptomics
  • Malignant transformation

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