Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer.

Autor: Aithal A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Junker WM; Sanguine Diagnostics and Therapeutics Inc. Omaha, NE, United States of America., Kshirsagar P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Das S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Kaur S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Orzechowski C; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Gautam SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Jahan R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Sheinin YM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America., Lakshmanan I; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America.; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America., Jain M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States of America.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 Apr 30; Vol. 13 (4), pp. e0193907. Date of Electronic Publication: 2018 Apr 30 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0193907
Abstrakt: MUC16 is overexpressed in ovarian cancer and plays important roles in invasion and metastasis. Previously described monoclonal antibodies against cell surface expressed MUC16 recognize the N-terminal tandemly repeated epitopes present in cancer antigen 125 (CA125). MUC16 is cleaved at a specific location, thus, releasing CA125 into the extracellular space. Recent reports have indicated that the retained carboxy-terminal (CT) fragment of MUC16 might play an important role in tumorigenicity in diverse types of cancers. However, limited data is available on the fate and existence of CT fragment on the surface of the cancer cell. Herein, we characterize two monoclonal antibodies (mAbs) showing specificity to the retained juxtamembrane region of MUC16. For the first time, we demonstrate that MUC16 is cleaved in ovarian cancer cells (NIH:OVCAR-3 [OVCAR-3]) and that the cleaved MUC16 subunits remain associated with each other. Immunohistochemical analyses on different grades of ovarian tumor tissues indicated differential reactivity of CA125 and MUC16 CT mAbs. The CA125 (M11) mAb detected 32/40 (80%), while the CT mAb (5E6) detected 33/40 (82.5%) of total ovarian cancer cases. For serous and serous papillary cases, the CA125 (M11) mAb stained 27/31 cases (87%), while CT mAb (5E6) stained 29/31 cases (93.5%). The CT mAb(s) accurately predict expression of MUC16 since their epitopes are not tandemly repeated and their reactivity may not be dependent on O-linked glycosylation. These antibodies can serve as valuable reagents for understanding MUC16 cleavage and may also serve as potential therapeutic agents for treatment of ovarian cancer.
Databáze: MEDLINE
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