Accession Number:

AD1000370

Title:

Molecular Characterization of Human MUC16 (CA125) in Breast Cancer

Descriptive Note:

Technical Report

Corporate Author:

University of Nebraska Medical Center Omaha, United States

Personal Author(s):

Report Date:

2015-04-01

Pagination or Media Count:

35.0

Abstract:

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.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE