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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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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DOI: https://doi.org/10.1038/sj.onc.1208756
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