1. ¹Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
2. ²Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
3. ³INSERM, Place de Verdun, 59045 Lille Cedex, France

Correspondence: SK Batra, sbatra@unmc.edu

Received 20 September 2004; Revised 1 April 2005; Accepted 1 April 2005; Published online 20 June 2005.

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- (IFN) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFN 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 -2 (TGF-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFN 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 IFN is partially inhibited by RA, IFN is shown to repress RA-driven TGF-2 induction, pointing to the involvement of alternative mechanism(s) in IFN–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 IFN/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.