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Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways

Oncogene volume 24, pages 6143–6154 (2005)Cite this article

Abstract

The transmembrane mucin, MUC4, is aberrantly expressed with a high incidence in human pancreatic adenocarcinomas and plays an important role in the pathogenesis of the disease. Our recent studies have shown that interferon-γ (IFNγ) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNγ occurs via a novel pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1), whereas its stimulation by RA requires mediation by the transforming growth factor β-2 (TGFβ-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNγ and RA in MUC4 regulation in pancreatic tumour cells. We demonstrate that these reagents exert a synergistic induction of MUC4. Interestingly, while the upregulation of STAT-1 by IFNγ is partially inhibited by RA, IFNγ is shown to repress RA-driven TGFβ-2 induction, pointing to the involvement of alternative mechanism(s) in IFNγ–RA synergism. Moreover, a dose-dependent and cooperative induction of MUC4 promoter activity suggests a regulation at the transcriptional level, most likely by STAT-1 and RAR/RXR (RA receptor/retinoic X receptor) or other IFNγ/RA-induced secondary intermediate effectors. Our findings provide potential mechanisms that may account for the aberrant expression of MUC4 in pancreatic tumour cells and expose a novel molecular mechanism of gene induction, whereby a reprogramming of signalling pathway through alternative route(s) operates during a synergistic interaction of biological modifiers.

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Acknowledgements

We thank Erik Moore (UNMC) for technical support and the Molecular Biology Core Facility for oligonucleotide synthesis and DNA sequencing. We also thank Dr JK Vishwanatha (UNMC) for the generous gift of anti-PGK antibody. The RARα-specific inhibitor, Ro41-5253, was a generous gift from Hoffman/LaRoche. This work was supported by a grant from the National Institutes of Health (CA 78590) and the Nebraska Department of Health LB506 Program (2002-04).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA

    Mahefatiana Andrianifahanana, Anshu Agrawal, Ajay P Singh, Nicolas Moniaux & Surinder K Batra

  2. Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA

    Isabelle van Seuningen & Jean-Pierre Aubert

  3. INSERM, Place de Verdun, Lille Cedex, 59045, France

    Jane Meza

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  1. Mahefatiana Andrianifahanana
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Correspondence to Surinder K Batra.

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Andrianifahanana, M., Agrawal, A., Singh, A. et al. Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways. Oncogene 24, 6143–6154 (2005). https://doi.org/10.1038/sj.onc.1208756

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