6. Oligosaccharide Moieties
Mucins such as CA125 are large proteins associated with extensive glycosylation that is important for structure and function (reviewed in [42]). In addition to the contradicting views regarding the molecular weight forms of CA125, the types of glycosylation reported are also controversial. Davis et al. identified CA125 as protein with, in comparison to other mucins, low carbohydrate content of 24%, constituting mostly mannose and N-linked glycans [35], while Hanisch et al. described CA125 as consisting of 68% carbohydrates, essentially mannose free and O-linked glycans [43].
A third view was presented by Nagata et al. in 1991 [44]. They found CA125 to be a glycosylphosphatidylinositol (GPI) anchored molecule with N- and O-linked glycan structures [44]. Independently, a study by Kui Wong et al. also found N- and O-linked glycans attached to CA125 [7]. Interestingly, one identified structure was identical to an unusual glycostructure expressed by uromodulin [7,45]. In light of our recent results these contradicting reports may arise from cross-reactivity of the M11-like and OC125-like antibodies with other proteins [41]. This may have lead to the characterization of proteins that were wrongly assigned as CA125.
Additionally, aberrant glycosylation of CA125 has been reported for various diseases. The study of Pastan et al. demonstrated increased presentation of Lewis y blood group tetrasaccharide (Ley) on ovarian cancer tissue compared with normal ovarian tissue [46]. This Ley modification, expressed in 75% of ovarian cancer tissue specimens, was identified as a part of the CA125 glycan structure [47]. Microheterogeneities in CA125 glycosylation may represent a possible diagnostic indicator, according to Jankovic et al., as differential glycosylation of CA125 derived from amniotic fluid and OVCAR-3 cells was demonstrated [48]. Furthermore, Mitic et al. reported differential binding of CA125 to a set of sialic acid-binding Ig-like lectins (Siglecs) depending on the source of the protein. A preference for Siglec-9 binding was evident for CA125 derived from an OVCAR-3 cell line [49]. Interestingly, this interaction has been shown to be necessary for the binding to and subsequent suppression of NK-cell function [8–11].