MUC16 mucin (CA125) regulates the formation of multicellular aggregates by altering β-catenin signaling

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 beta-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 beta-catenin relocation from the cell membrane to the cytoplasm, decreases its expression by increasing degradation and decreases beta-catenin target gene expression. MUC16 CTD inhibits GSK-3 beta-mediated phosphorylation and degradation of beta-catenin, leading to increased beta-catenin levels. Importantly, knockdown of beta-catenin inhibited multicellular aggregation. These findings indicate that MUC16 promotes the formation of multicellular aggregates by inhibiting beta-catenin degradation.