MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway
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Audrey Bouillez1,*, Viviane Gnemmi1,2,3,*, Kelly Gaudelot1, Brigitte Hémon1, Bélinda Ringot1, Nicolas Pottier2,4, François Glowacki4,5, Caroline Butruille6, Christelle Cauffiez2,4, Malika Hamdane7, Nicolas Sergeant7, Isabelle Van Seuningen1, Xavier Leroy1,2,3, Sébastien Aubert1,2,3,*, Michaël Perrais1,2,*
1 Inserm, UMR837, Equipe 5 “Mucines, différenciation et cancérogenèse épithéliales”, Jean-Pierre Aubert Research Center, Lille Cedex, France
2 Faculté de Médecine, Université de Lille 2, Lille Cedex, France
3 Institute of Pathology, Centre de Biologie-Pathologie, CHRU de Lille, Lille Cedex, France
4 EA4483, Faculté de Médecine, Pole Recherche, Lille Cedex, France
5 Department of Nephrology, CHRU de Lille, Lille Cedex, France
6 Department of Urology, CHRU de Lille, Lille Cedex, France
7 Inserm, UMR837, Equipe 1 “Alzheimer and Tauopathies”, Jean-Pierre Aubert Research Center, Lille Cedex, France
* Denotes equal contribution
Michaël Perrais, email:
Keywords: MUC1, kidney cancer, ADAM10, ADAM17, γ-secretase, invasion.
Received: January 16, 2014 Accepted: January 31, 2014 Published: February 2, 2014
MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties. Using shRNA strategy and/or different MUC1 constructs, we found that MUC1-extracellular domain and MUC1-CT are involved in increase of migration, cell viability, resistance to anoikis and in decrease of cell aggregation in cancer cells. Invasiveness depends only on MUC1-CT. Then, by using siRNA strategy and/or pharmacological inhibitors or peptides, we showed that sheddases ADAM10, ADAM17 and gamma-secretase are necessary for MUC1 C-terminal subunit (MUC1-C) nuclear location and in increase of invasion property. Finally, MUC1 overexpression increases ADAM10/17 protein expression suggesting a positive regulatory loop. In conclusion, we report that MUC1 acts in renal cancer progression and MUC1-C nuclear localization drives invasiveness of cancer cells through a sheddase/gamma secretase dependent pathway. MUC1 appears as a therapeutic target by blocking MUC1 cleavage or nuclear translocation by using pharmacological approach and peptide strategies.
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