Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways
Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways
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DOI：
10.1038/sj.onc.1208756
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发表时间：
2005-09-08
期刊：
影响因子：
8
通讯作者：
Batra, SK
中科院分区：
文献类型：
--
作者：
Andrianifahanana, M;Agrawal, A;Batra, SK
跨膜粘蛋白MUC 4在胰腺癌中异常表达，在胰腺癌的发病机制中起重要作用。我们最近的研究表明，干扰素-γ（IFN-γ）和视黄酸（RA）是胰腺肿瘤细胞中MUC 4的重要调节剂。IFN γ对MUC 4的诱导通过一种新的途径发生，该途径涉及信号转导和转录激活因子1（STAT-1）的上调，而RA对MUC 4的刺激需要转化生长因子β-2（TGF β-2）的介导。在这项研究中，我们已经调查了潜在的相互作用的IFN γ和RA在胰腺肿瘤细胞MUC 4调节的分子机制。我们证明，这些试剂发挥协同诱导MUC 4。有趣的是，虽然STAT-1通过IFN γ的上调被RA部分抑制，但IFN γ显示出抑制RA驱动的TGF β-2诱导，这表明在IFN γ-RA协同作用中涉及替代机制。此外，MUC 4启动子活性的剂量依赖性和协同诱导表明在转录水平上的调节，最有可能是通过STAT-1和RAR/RXR（RA受体/视黄酸X受体）或其他IFN γ/RA诱导的次级中间效应物。我们的研究结果提供了可能解释胰腺肿瘤细胞中MUC 4异常表达的潜在机制，并揭示了基因诱导的新分子机制，即在生物修饰剂的协同相互作用期间，通过替代途径对信号传导途径进行重编程。
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 ( IFN gamma) and retinoic acid ( RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFN gamma 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 ( TGF beta-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFN gamma 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 gamma is partially inhibited by RA, IFN gamma is shown to repress RA-driven TGFb-2 induction, pointing to the involvement of alternative mechanism( s) in IFN gamma-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 gamma/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.