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Carcinogenesis Advance Access published online on July 9, 2007
Carcinogenesis, doi:10.1093/carcin/bgm158
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transcription Factor AP-2{alpha} Represses Both the Mucin MUC4 Expression and Pancreatic Cancer Cell Proliferation

Valérie Fauquette1,2, Sébastien Aubert1,2,4, Sophie Groux-Degroote3, Brigitte Hemon1,2, Nicole Porchet1,2,4, Isabelle Van Seuningen1,2 and Pascal Pigny1,2,4

1 INSERM, U837, Place de Verdun, 59045 Lille cedex, France
2 Université de Lille 2, Faculté de médecine, Centre de Recherche Jean-Pierre Aubert, Place de Verdun, 59045 Lille cedex, France
3 UMR CNRS 8576, Université des Sciences et Technologies de Lille 1, 59655 Villeneuve d'Ascq cedex, France
4 Centre Hospitalier Régional et Universitaire, 59037 Lille cedex, France

Address correspondence to: Pascal Pigny, INSERM U837, place de Verdun, 59045 Lille cedex, France. Tel 33 3 202 988 50; Fax 33 3 205 385 62; E-mail: pigny{at}lille.inserm.fr

MUC4 is a transmembrane mucin expressed in pancreatic ductal adenocarcinoma (DAC) in contrast with normal pancreas, and is an independent predictor of poor prognosis in patients with invasive DAC. Our aim was therefore to investigate the mechanisms that control MUC4 expression in pancreatic cancer cells. We focused our study on AP-2{alpha} (activator protein-2{alpha}) transcription factor that acts as a tumor suppressor gene in several cancers. In a series of 18 human DAC, using immunohistochemistry, we confirmed that MUC4 was exclusively expressed in cancerous or preneoplastic lesions in 83% of the samples. On the contrary, AP-2 was mainly expressed by non tumoral ductal cells (61%) or endocrine cells (67%). Moreover, MUC4 and AP-2 were never found co-expressed suggesting an inhibitory role of AP-2{alpha} in normal ductal cells. In CAPAN-1 and CAPAN-2 cells, transient AP-2{alpha} over-expression decreased both MUC4 mRNA and apomucin levels by 20%-40% by a mechanism involving inhibition of MUC4 promoter. By chromatin immunoprecipitation and gel-shift assays, we demonstrated that this inhibition involved two AP-2 cis-elements located in the -475/-238 region of the promoter. CAPAN-1 clones, that stably over-expressed AP-2{alpha}, displayed a strong MUC4 down-regulation (-38% to -100%), a significant decrease of both cell proliferation and invasion concomitant to the up-regulation of p27 cdk-inhibitor. In conclusion, our data provide evidence that AP-2{alpha} is an important in vivo negative regulator of MUC4 expression in human pancreatic tissue and that AP-2{alpha} may play a tumor suppressive role in pancreatic DAC.

Received February 12, 2007; revised June 4, 2007; accepted July 3, 2007.


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