A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-b in pancreatic carcinogenesis
Résumé
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-b, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcino-genesis 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-b in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4 þ /Smad4À), CAPAN-2 (MUC4 þ / Smad4 þ) and PANC-1 (MUC4À/Smad4 þ), were used. By RT-PCR, transfection assays and immunohistochem-istry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-b, (ii) Smad2 positively cooperates with Smad4 to activate the promoter , (iii) activation of Smad4 by exogenous TGF-b induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-b 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-b is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-b as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.
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