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Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis

Oncogene volume 35, pages 2496–2505 (2016)Cite this article

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Abstract

In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

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Acknowledgements

We thank Dimitra Vyrla (University of Crete Medical School), Triantafyllos Liloglou (University of Liverpool) and Maria Denis (Biomedcode Hellas SA) for helpful discussions. This work was supported by the European Commission (EC) research program Inflammation and Cancer Research in Europe (INFLA-CARE; EC contract number 223151) to AGE and Almac Diagnostics and the EC REGPOT support program Translational Potential (TransPOT; EC contract number 285948) to AGE, KP, II and DK.

Author contributions

KKG and MI contributed equally to this work. KKG, MI, AS, KG, GN, DCK, DK and ED contributed to acquisition, analysis and interpretation of experimental data and critical reading of the manuscript; SM and FAM performed the gene expression profiling and contributed to in silico analysis of results; GAP and II contributed to bioinformatic analyses and critically reviewed the manuscript; KAP, DK and ED contributed to interpretation of experimental data and critically reviewed the manuscript; AGE contributed to conception, design, analysis and interpretation of data and drafting of the manuscript.

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Authors and Affiliations

  1. Division of Basic Sciences, Molecular and Cellular Biology Laboratory, University of Crete Medical School, Heraklion, Greece

    K K Gkouskou, K Georgila, A Siganou, G Nikolaidis, D C Kanellis & A G Eliopoulos

  2. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece

    M Ioannou, D Kardassis & A G Eliopoulos

  3. Division of Basic Sciences, Bioinformatics and Computational Biology Laboratory, University of Crete Medical School, Heraklion, Greece

    G A Pavlopoulos & I Iliopoulos

  4. Almac Diagnostics, Craigavon, UK

    S Moore & F A McDyer

  5. Department of Gastroenterology, University of Crete Medical School, Heraklion, Greece

    K A Papadakis

  6. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    K A Papadakis

  7. Division of Basic Sciences, Laboratory of Biochemistry, University of Crete Medical School, Heraklion, Greece

    D Kardassis

  8. Department of Pathology, University of Crete Medical School, Heraklion, Greece

    E Drakos

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  1. K K Gkouskou
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Correspondence to A G Eliopoulos.

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Gkouskou, K., Ioannou, M., Pavlopoulos, G. et al. Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis. Oncogene 35, 2496–2505 (2016). https://doi.org/10.1038/onc.2015.307

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