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J. Biol. Chem., Vol. 278, Issue 31, 28619-28634, August 1, 2003
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Characterization of the Oligosaccharides Associated with the Human Ovarian Tumor Marker CA125*
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From the
Department of Biological Sciences,
Imperial College of Science, Technology and Medicine, London SW7 2AY, United
Kingdom, the ¶Department of Physiological
Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23501-1980, and
the ||M-SCAN Mass Spectrometry Research and
Training Centre, Silwood Park, Ascot SL5 7PZ, United Kingdom
CA125 is a mucin commonly employed as a diagnostic marker for epithelial ovarian cancer. Induction of humoral responses to CA125 leads to increased survival times in patients with this form of cancer, suggesting a potential role for this mucin in tumor progression. In this study, oligosaccharides linked to CA125 derived from the human ovarian tumor cell line OVCAR-3 were subjected to rigorous biophysical analysis. Sequencing of the O-glycans indicates the presence of both core type 1 and type 2 glycans. An unusual feature is the expression of branched core 1 antennae in the core type 2 glycans. CA125 is also N-glycosylated, expressing primarily high mannose and complex bisecting type N-linked glycans. High mannose type glycans include Man5-Man9GlcNAc2. The predominant N-glycans are the biantennary, triantennary, and tetraantennary bisecting type oligosaccharides. Remarkably, the N-glycosylation profiles of CA125 and the envelope glycoprotein gp120 (derived from H9 lymphoblastoid cells chronically infected with HIV-1) are very similar. The CA125-associated N-glycans have also recently been implicated in crucial recognition events involved in both the innate and adaptive arms of the cell-mediated immune response. CA125 may therefore induce specific immunomodulatory effects by employing its carbohydrate sequences as functional groups, thereby promoting tumor progression. Immunotherapy directed against CA125 may attenuate these immunosuppressive effects, leading to the prolonged survival of patients with this extremely serious form of cancer.
Received for publication, March 18, 2003 , and in revised form, May 5, 2003.
* This work was supported by Jeffress Research Grant J-584 and the Elsa U. Pardee Foundation (to M. S. P.), the Biotechnology and Biological Sciences Research Council and the Wellcome Trust (to A. D. and H. R. M.), and National Institutes of Health Grant R01 HD35652 (to G. F. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a Malaysian Government Scholarship.
** Member of the Consortium for Functional Glycomics supported by NIGMS, National Institutes of Health and to whom correspondence may be addressed. Tel.: 757-446-5653; Fax: 757-624-2269; E-mail: clarkgf{at}evms.edu.
Member of the Consortium for Functional Glycomics supported by NIGMS, National
Institutes of Health and to whom correspondence may be addressed. Tel.:
44-207-225-5219; Fax: 44-207-225-0458; E-mail:
a.dell{at}ic.ac.uk.
To whom correspondence may be addressed. Tel.: 757-446-5755; Fax:
757-624-2269; E-mail:
pantankms{at}evmsmail.evms.edu.
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