Synergistic induction of the MUC4 mucin gene by interferon-gamma and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways.
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-gamma (IFNgamma) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNgamma 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 beta-2 (TGFbeta-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNgamma 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 IFNgamma is partially inhibited by RA, IFNgamma is shown to repress RA-driven TGFbeta-2 induction, pointing to the involvement of alternative mechanism(s) in IFNgamma-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 IFNgamma/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.
Andrianifahanana
Mahefatiana
M
Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Agrawal
Anshu
A
Singh
Ajay P
AP
Moniaux
Nicolas
N
van Seuningen
Isabelle
I
Aubert
Jean-Pierre
JP
Meza
Jane
J
Batra
Surinder K
SK
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D055264:Mucin-4; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation; D000097768:Retinoic Acid Receptor gamma
D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D055264:Mucin-4; D009077:Mucins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C524658:MUC4 protein, human; C000607071:RARA protein, human; C494079:STAT1 protein, human