title: MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway.
abstract: 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.
authors: Inserm, UMR837, Equipe 5 "Mucines, différenciation et cancérogenèse épithéliales", Jean-Pierre Aubert Research Center, Lille Cedex, France.
authors: Audrey
authors: A
authors: Bouillez
authors: Viviane
authors: V
authors: Gnemmi
authors: Kelly
authors: K
authors: Gaudelot
authors: Brigitte
authors: B
authors: Hémon
authors: Bélinda
authors: B
authors: Ringot
authors: Nicolas
authors: N
authors: Pottier
authors: François
authors: F
authors: Glowacki
authors: Caroline
authors: C
authors: Butruille
authors: Christelle
authors: C
authors: Cauffiez
authors: Malika
authors: M
authors: Hamdane
authors: Nicolas
authors: N
authors: Sergeant
authors: Isabelle
authors: I
authors: Van Seuningen
authors: Xavier
authors: X
authors: Leroy
authors: Sébastien
authors: S
authors: Aubert
authors: Michaël
authors: M
authors: Perrais
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D064593:Heterografts; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D015398:Signal Transduction; D014162:Transfection
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D021122:Protein Subunits; D053829:Amyloid Precursor Protein Secretases