Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia
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Frida Danielsson1, Erik Fasterius2, Devin Sullivan1, Linnea Hases1,5, Kemal Sanli1, Cheng Zhang1, Adil Mardinoglu1, Cristina Al-Khalili2, Mikael Huss3, Mathias Uhlén1,2,4, Cecilia Williams1,5 and Emma Lundberg1
1Science for Life Laboratory, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm SE-171 21, Sweden
2Department of Proteomics, KTH, Royal Institute of Technology, Stockholm SE-106 91, Sweden
3Department of Biochemistry and Biophysics, Stockholm University, Solna SE-171 21, Sweden
4Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm DK-2970, Denmark
5Department of Biosciences and Nutrition, Karolinska Institute, Huddinge SE-141 57, Sweden
Emma Lundberg, email: [email protected]
Frida Danielsson, email: [email protected]
Keywords: hypoxia; transcriptomics; malignant transformation
Received: September 08, 2017 Accepted: February 24, 2018 Published: April 13, 2018
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.
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