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A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis

Oncogene volume 23, pages 5729–5738 (2004)Cite this article

Abstract

MUC4 encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-β, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-β in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4−), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4−/Smad4+), were used. By RT–PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-β, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-β induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-β activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-β is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-β as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.

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Acknowledgements

We are indebted to Marie-Paule Ducourouble, Brigitte Hémon and Audrey Vincent for their excellent technical help. We would like to thank Dr Azzedine Atfi (Unité INSERM N°482, Paris) for the kind gifts of pCMV-Smad2, pcDNA3/Myc-Smad3, pcDNA3/HA-Smad4, pcDNA3-Smad7 expression vectors and Dr Myasoko (University of Tokyo, Japan) for the gift of pcDNA3-c-Ski expression vector. This work was supported by grants from l'Association de Recherche contre le Cancer (IVS, No 5785), from la Ligue Régionale du Pas de Calais contre le Cancer (IVS) and by an RO1 grant CA78590 from the National Institutes of Health (SKB). N Jonckheere is the recipient of a CHRU de Lille-Région Nord-Pas de Calais PhD fellowship.

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Authors and Affiliations

  1. Unité INSERM 560, Place de Verdun, Lille Cedex, 59045, France

    Nicolas Jonckheere, Michaël Perrais, Christophe Mariette, Jean-Pierre Aubert, Pascal Pigny & Isabelle Van Seuningen

  2. Department of Biochemistry and Molecular Biology, UNMC/Eppley Cancer Center, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, NE, USA

    Surinder K Batra

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  1. Nicolas Jonckheere
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Correspondence to Isabelle Van Seuningen.

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Jonckheere, N., Perrais, M., Mariette, C. et al. A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis. Oncogene 23, 5729–5738 (2004). https://doi.org/10.1038/sj.onc.1207769

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