The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.

Nicolas Jonckheere 1, * Nicolas Skrypek 1 Johann Merlin 1 Anne Frédérique Dessein 1 Patrick Dumont 2 Emmanuelle Leteurtre 3 Ann Harris 4, 5 Jean-Luc Desseyn 6 Christiane Susini 7 Frédéric Frénois 1 Isabelle Van Seuningen 1
* Auteur correspondant
1 Inserm UMR837 Team 5
Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer
2 IBLI - Institut de biologie de Lille - IBL
3 Inserm UMR837 Team 5
Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Centre de biologie pathologie [Lille], CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
4 Human Molecular Genetics Program
5 Department of Pediatrics
6 Equipe 5
Inflammation: mécanismes et régulation et interactions avec la nutrition et les candidoses, Université Lille Nord de France
7 I2MR - Institut de médecine moléculaire de Rangueil
Abstract : The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells.
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PLoS ONE, Public Library of Science, 2012, 7 (2), pp.e32232. 〈10.1371/journal.pone.0032232〉
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Nicolas Jonckheere, Nicolas Skrypek, Johann Merlin, Anne Frédérique Dessein, Patrick Dumont, et al.. The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.. PLoS ONE, Public Library of Science, 2012, 7 (2), pp.e32232. 〈10.1371/journal.pone.0032232〉. 〈inserm-00807830〉

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