CA125 (MUC16) gene silencing suppresses growth properties of ovarian and breast cancer cells

Abstract

The tumour-associated antigen CA125 (mucin 16, MUC16) is commonly expressed in ovarian cancer, and can also be detected in other tumour of epithelial origin, but its physiological role is largely unknown. The aim of the present study was to investigate the impact of MUC16 gene silencing on the growth properties of ovarian and breast cancer cells. We analysed cellular effects linked to oncogenesis, such as proliferation, cell cycle and apoptosis, after transient and stable transfection with MUC16 short hairpin RNA (shRNA) in diverse epithelial cancer cell lines with different MUC16 expression. Furthermore, alterations in cell adhesion, migration and invasion were evaluated in stable MUC16 knockdown clones. The growth of all tested MUC16+ tumour cells was significantly suppressed by induction of caspase-dependent apoptosis after transient transfection with MUC16 shRNA, irrespective of the initial MUC16 expression level and cancer origin. Growth inhibition could be confirmed in stable MUC16 knockdown clones, albeit caspase-dependent death pathways seemed no longer be activated. In MUC16low+ ovarian cancer cells, stable MUC16 gene silencing resulted in a substantial blockade of colony formation, cell adhesion, migration and invasiveness associated with reduced activation of metalloproteinases-2 (MMP-2). By contrast, the tested MUC16high+ cell lines displayed a non-motile and non-invasive phenotype which was not affected by MUC16 knockdown, probably due to the expression of different MUC16 isoforms with divergent functions in individual cell lines. Our results provide evidence for a central role of MUC16 in cancer cell survival pathways. Additionally, MUC16 might also be involved in adhesion, migration and invasion depending on the type of cancer cell.