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

M. Andrianifahanana, A. P. Singh, C. Nemos, M. P. Ponnusamy, N. Moniaux, Parmender P Mehta, G. C. Varshney, S. K. Batra

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38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7251-7261
Number of pages11
JournalOncogene
Volume26
Issue number51
DOIs
StatePublished - Nov 8 2007

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Keywords

  • IFN-γ
  • MUC4
  • Pancreatic cancer
  • Regulation
  • STAT-1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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