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Proteomic and Postproteomic Characterization of Keratan Sulfate-Glycanated Isoforms of Thyroglobulin and Transferrin Uniquely Elaborated by Papillary Thyroid Carcinomas.

Magro, Gaetano and Perissinotto, Daniela and Schiappacassi, Monica and Goletz, Steffen and Otto, Albrecht and Müller, Eva-Christina and Bisceglia, Michele and Brown, Gavin and Ellis, Timothy and Grasso, Sebastiano and Colombatti, Alfonso and Perris, Roberto (2003) Proteomic and Postproteomic Characterization of Keratan Sulfate-Glycanated Isoforms of Thyroglobulin and Transferrin Uniquely Elaborated by Papillary Thyroid Carcinomas. American Journal of Pathology, 163 (1). pp. 183-196. ISSN 0002-9440

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    Abstract

    Previous studies have suggested that surface components of papillary thyroid carcinoma (PTC) cells may be aberrantly glycanated, but the precise nature of these molecules has not been unveiled nor documented to be of clinical relevance. A monoclonal antibody was raised against a unique keratan sulfate (KS) determinant and used to differentially screen benign and malignant thyroid tissue for the expression of components carrying these moieties. In a total of 349 cases of benign and malignant thyroid lesions, 100% of the 115 PTC cases examined (including various histological subtypes) were found to contain KS-bearing molecules, whereas these were virtually absent from benign tissues and other thyroid tumors, with the exception of 21% of the follicular carcinoma cases analyzed. A composite immunoaffinity chromatography, immunochemistry, and mass spectrometric approach revealed that the PTC-specific KS-bearing macromolecules were unique glycoforms of thyroglobulin and transferrin. Combined, reciprocal immunoprecipitation and Western blotting further indicated that the former glycoform predominated and that most of the transferrin produced by PTC was glycanated with KS moieties. Fluorescent keratanase II-based fingerprinting of the KS moieties bound to these isoforms further demonstrated several PTC-specific peculiarities: 1) that a considerable portion of the moieties was covalently attached via a novel core protein linkage structure; 2) they had an unusual extended average length; 3) an unusual relative ratio of highly sulfated disaccharides terminating with (2-3)-linked N-acetylneuraminic acid capping residues; and 4) a novel unidentified oligosaccharide moiety at the nonreducing terminus. Comparative analysis of the relative distribution of transferrin in benign versus PTC tissues highlighted a marked malignancy-associated abundance of the molecule, with a >75% frequency in expression in PTC. These findings demonstrate that PTC cells synthesize unique post-translationally modified thyroglobulin and transferrin variants in situ that may be directly exploitable for diagnosis, through histological and noninvasive cytological procedures; for devising novel strategies for antibody-guided imaging of this tumor in vivo; and for postsurgery follow-up of PTC patients.

    Item Type: Article
    Journal or Publication Title: American Journal of Pathology
    Subjects: Q Science > QH Natural history > QH301 Biology
    Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
    VC's Office
    Faculty of Science and Technology > Lancaster Environment Centre
    ID Code: 13104
    Deposited By: Dr Gavin M Brown
    Deposited On: 05 Sep 2008 11:06
    Refereed?: Yes
    Published?: Published
    Last Modified: 26 Jul 2012 15:05
    Identification Number:
    URI: http://eprints.lancs.ac.uk/id/eprint/13104

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    • Proteomic and Postproteomic Characterization of Keratan Sulfate-Glycanated Isoforms of Thyroglobulin and Transferrin Uniquely Elaborated by Papillary Thyroid Carcinomas. (deposited 05 Sep 2008 11:06)[Currently Displayed]

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