Molecular Characterization of Human MUC16 (CA125) in Breast Cancer
University of Nebraska Medical Center Omaha, United States
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MUC16, precursor of the most widely used ovarian cancer biomarker CA125, is up-regulated in multiple malignancies and is associatedwith poor prognosis. While the pro-tumorigenic and metastatic roles of MUC16 are ascribed to the cell-associated carboxyl-terminalMUC16 MUC16-Cter, the exact biochemical nature of MUC16 cleavage generating MUC16-Cter has remained unknown. Using differentlengths of dual-epitope N-terminal FLAG- and C-terminal HA-Tag tagged C-terminal MUC16 fragments, we demonstrate that MUC16cleavage takes place in the juxta-membrane ectodomain stretch of twelve amino acids that generates a 17 kDa cleaved product and isdistinct from the predicted sites. This was further corroborated by domain swapping experiment. Further, the cleavage of MUC16 wasfound to take place in the Golgipost-Golgi compartments and is dependent on the acidic pH in the secretory pathway. A similar pattern of17 kDa cleaved MUC16 was observed in multiple cell types eliminating the possibility of cell type specific phenomenon. MUC16-Ctertranslocates to the nucleus in a cleavage dependent manner and binds to the chromatin suggesting its involvement in regulation of geneexpression. Taken together, we demonstrate for the first time the oft-predicted cleavage of MUC16 that is critical in devising successfultherapeutic interventions based on MUC16.
- Medicine and Medical Research