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IFN-γ-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-γ response

Oncogene volume 26, pages 7251–7261 (2007)Cite this article

Abstract

MUC4 is a transmembrane mucin, which is aberrantly expressed in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. Here, we present a novel mechanism of IFN-γ-induced expression of MUC4 in pancreatic cancer cells. Our studies highlight the upregulation of STAT-1 as a basis for MUC4 induction and demonstrate that its activation and upregulation by IFN-γ are two distinct, albeit temporally integrated, signalling events that drive the selective induction of IRF-1 and MUC4, respectively, within a single cell system. The profile of interferon regulatory factor (IRF)-1 gene induction by IFN-γ is consistent with its rapid transactivation by phospho-Y701-STAT-1. In contrast, the induction of the MUC4 mucin gene expression is relatively delayed, and occurs only in response to an increase in STAT-1 expression. A progressive binding of STAT-1 to various γ-interferon-activated sequences (GAS) in the MUC4 promoter is observed in chromatin immunoprecipitation assay, indicating its direct association. Stimulation of STAT-1 expression by double-stranded polynucleotides or ectopic expression is shown to induce MUC4 expression, without Y701 phosphorylation of STAT-1. This effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of STAT-1 expression, supporting further the relevance of STAT-1 in MUC4 regulation. In conclusion, our findings identify a novel mechanism for MUC4 regulation in pancreatic cancer cells and unfold new perspectives on the foundation of IFN-γ-dependent gene regulation.

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References

  • Andrianifahanana M, Moniaux N, Schmied BM, Ringel J, Friess H, Hollingsworth MA et al. (2001). Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significance. Clin Cancer Res 7: 4033–4040.

    CAS  PubMed  Google Scholar 

  • Boehm U, Klamp T, Groot M, Howard JC . (1997). Cellular responses to interferon-gamma. Annu Rev Immunol 15: 749–795.

    Article  CAS  Google Scholar 

  • Chatterjee-Kishore M, Wright KL, Ting JP, Stark GR . (2000). How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene. EMBO J 19: 4111–4122.

    Article  CAS  Google Scholar 

  • Choudhury A, Singh RK, Moniaux N, El-Metwally TH, Aubert JP, Batra SK . (2000). Retinoic acid-dependent transforming growth factor-beta 2-mediated induction of MUC4 mucin expression in human pancreatic tumor cells follows retinoic acid receptor-alpha signaling pathway. J Biol Chem 275: 33929–33936.

    Article  CAS  Google Scholar 

  • Darnell Jr JE . (1997). STATs and gene regulation. Science 277: 1630–1635.

    Article  CAS  Google Scholar 

  • Darnell Jr JE, Kerr IM, Stark GR . (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421.

    Article  CAS  Google Scholar 

  • Decker T, Kovarik P . (2000). Serine phosphorylation of STATs. Oncogene 19: 2628–2637.

    Article  CAS  Google Scholar 

  • Goh KC, Haque SJ, Williams BR . (1999). p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J 18: 5601–5608.

    Article  CAS  Google Scholar 

  • Guo GG, Patel K, Kumar V, Shah M, Fried VA, Etlinger JD et al. (2002). Association of the chaperone glucose-regulated protein 58 (GRP58/ER-60/ERp57) with Stat3 in cytosol and plasma membrane complexes. J Interferon Cytokine Res 22: 555–563.

    Article  CAS  Google Scholar 

  • Kalvakolanu DV, Borden EC . (1996). An overview of the interferon system: signal transduction and mechanisms of action. Cancer Invest 14: 25–53.

    Article  CAS  Google Scholar 

  • Lagow EL, Carson DD . (2002). Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-gamma and tumor necrosis factor-alpha. J Cell Biochem 86: 759–772.

    Article  CAS  Google Scholar 

  • Lee KA, Green MR . (1990). Small-scale preparation of extracts from radiolabeled cells efficient in pre-mRNA splicing. Methods Enzymol 181: 20–30.

    Article  CAS  Google Scholar 

  • Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W et al. (2005). Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 17: 761–771.

    Article  CAS  Google Scholar 

  • Marg A, Shan Y, Meyer T, Meissner T, Brandenburg M, Vinkemeier U . (2004). Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1. J Cell Biol 165: 823–833.

    Article  CAS  Google Scholar 

  • Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z et al. (1996). Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379: 645–648.

    Article  CAS  Google Scholar 

  • Meyer T, Marg A, Lemke P, Wiesner B, Vinkemeier U . (2003). DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1. Genes Dev 17: 1992–2005.

    Article  CAS  Google Scholar 

  • Nelson JD, Denisenko O, Sova P, Bomsztyk K . (2006). Fast chromatin immunoprecipitation assay. Nucleic Acids Res 34: e2.

    Article  Google Scholar 

  • Perrais M, Pigny P, Ducourouble MP, Petitprez D, Porchet N, Aubert JP et al. (2001). Characterization of human mucin gene MUC4 promoter: importance of growth factors and proinflammatory cytokines for its regulation in pancreatic cancer cells. J Biol Chem 276: 30923–30933.

    Article  CAS  Google Scholar 

  • Shuai K, Stark GR, Kerr IM, Darnell Jr JE . (1993). A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science 261: 1744–1746.

    Article  CAS  Google Scholar 

  • Singh AP, Chaturvedi P, Batra SK . (2007). Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Res 67: 433–436.

    Article  CAS  Google Scholar 

  • Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK . (2004). Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Res 64: 622–630.

    Article  CAS  Google Scholar 

  • Suzuki K, Mori A, Ishii KJ, Saito J, Singer DS, Klinman DM et al. (1999). Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc Natl Acad Sci USA 96: 2285–2290.

    Article  CAS  Google Scholar 

  • Swartz MJ, Batra SK, Varshney GC, Hollingsworth MA, Yeo CJ, Cameron JL et al. (2002). MUC4 expression increases progressively in pancreatic intraepithelial neoplasia. Am J Clin Pathol 117: 791–796.

    Article  Google Scholar 

  • Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE et al. (2005). Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 65: 939–947.

    CAS  PubMed  Google Scholar 

  • Zhou Y, Wang S, Gobl A, Oberg K . (2001). Interferon alpha induction of Stat1 and Stat2 and their prognostic significance in carcinoid tumors. Oncology 60: 330–338.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported, in part, by an R01 grant CA78590 from the National Institutes of Health. We are grateful to Dr Robert Arceci (Johns Hopkins University) for providing the STAT-1 plasmid construct. We also thank Kristi LW Berger (Eppley Institute) for editorial assistance. This work was supported by an RO1 grant CA78590 from the National Institutes of Health.

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Author notes

  1. A P Singh, C Nemos and M P Ponnusamy: These authors contributed equally to this work.

Authors and Affiliations

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

    M Andrianifahanana, A P Singh, C Nemos, M P Ponnusamy, N Moniaux, P P Mehta & S K Batra

  2. Cell Biology and Immunology, Institute of Microbial Technology, Chandigarh, India

    G C Varshney & S K Batra

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  1. M Andrianifahanana
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  2. A P Singh
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  5. N Moniaux
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Correspondence to S K Batra.

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Andrianifahanana, M., Singh, A., Nemos, C. et al. IFN-γ-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-γ response. Oncogene 26, 7251–7261 (2007). https://doi.org/10.1038/sj.onc.1210532

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