title: MUC16 mucin (CA125) regulates the formation of multicellular aggregates by altering β-catenin signaling.
abstract: After shedding from the primary tumor site, ovarian cancer cells form three-dimensional multicellular aggregates that serve as vehicle for cancer cell dissemination in the peritoneal cavity. MUC16 mucin (CA125) is aberrantly expressed by most advanced serous ovarian cancers and can promote proliferation, migration and metastasis. MUC16 associates with E-cadherin and β-catenin, two proteins involved in regulation of cell adhesion and the formation of multicellular aggregates. However, the role of MUC16 in the formation of multicellular aggregates remains to be defined. Here, we show that MUC16 alters E-cadherin cellular localization and expression. Consistent with this, MUC16 knockdown inhibited the formation of multicellular aggregates and, conversely, forced expression of MUC16 C-terminal domain (CTD) enhanced the formation of multicellular aggregates. MUC16 knockdown induces β-catenin relocation from the cell membrane to the cytoplasm, decreases its expression by increasing degradation and decreases β-catenin target gene expression. MUC16 CTD inhibits GSK-3β-mediated phosphorylation and degradation of β-catenin, leading to increased β-catenin levels. Importantly, knockdown of β-catenin inhibited multicellular aggregation. These findings indicate that MUC16 promotes the formation of multicellular aggregates by inhibiting β-catenin degradation.
authors: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke 3001, 12 ième Avenue Nord, Sherbrooke, Canada J1H 5N4.
authors: Panagiota
authors: P
authors: Giannakouros
authors: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke 3001, 12 ième Avenue Nord, Sherbrooke, Canada J1H 5N4.
authors: Marina
authors: M
authors: Comamala
authors: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke 3001, 12 ième Avenue Nord, Sherbrooke, Canada J1H 5N4.
authors: Isabelle
authors: I
authors: Matte
authors: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke 3001, 12 ième Avenue Nord, Sherbrooke, Canada J1H 5N4.
authors: Claudine
authors: C
authors: Rancourt
authors: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke 3001, 12 ième Avenue Nord, Sherbrooke, Canada J1H 5N4.
authors: Alain
authors: A
authors: Piché
keywords: B-catenin; E-cadherin; MUC16; membrane-bound mucin; multicellular aggregates; ovarian cancer
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