title: Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies.
abstract: The identification of high-risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging. Our study was conducted to analyze whether the quantification of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator receptor (u-PAR) and transcription factor binding to the u-PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors. Tumor/normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas (papillary, medullary, follicular and anaplastic, PTC, MTC, FTC and ATC) or follicular adenomas. U-PAR, MMP-1, MMP-7 and MMP-9 amounts were determined by ELISA, and transcription factor binding was determined by electrophoretic mobility shift assay. Binding of transcription factors to the u-PAR promoter was observed, but not associated with u-PAR expression. Carcinomas except MTC expressed significantly more u-PAR/MMPs than adenomas/normal tissues, this being associated with advanced pT- or M-stages. MMP-1 and MMP-9 were significantly higher in follicular carcinomas than in adenomas. In carcinomas, high u-PAR-gene expression correlated significantly with high MMP-9, the latter being associated with MMP-7 in normal tissues. Poor survival in differentiated tumors was associated in trend (p = 0.07); poor survival of all patients (p = 0.043) and especially of patients with carcinomas of follicular origin (including ATC), but not medullary carcinomas, were significantly associated with high u-PAR-protein (p = 0.015). Quantification of u-PAR is of prognostic relevance in thyroid carcinomas of non-c-cell origin, and u-PAR in part may be regulated nontranscriptionally in thyroid cancers. This is the first study to suggest MMP-1/-9 as significant differentiation markers between follicular adenoma and follicular carcinoma.
authors.affiliation: Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Mannheim Faculty, University of Heidelberg, and DKFZ Heidelberg, Mannheim, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Buergy
authors.forename: Theresia
authors.initials: T
authors.lastname: Weber
authors.forename: Gabriele D
authors.initials: GD
authors.lastname: Maurer
authors.forename: Giridhar
authors.initials: G
authors.lastname: Mudduluru
authors.forename: Fabian
authors.initials: F
authors.lastname: Medved
authors.forename: Joerg H
authors.initials: JH
authors.lastname: Leupold
authors.forename: Michael
authors.initials: M
authors.lastname: Brauckhoff
authors.forename: Stefan
authors.initials: S
authors.lastname: Post
authors.forename: Henning
authors.initials: H
authors.lastname: Dralle
authors.forename: Heike
authors.initials: H
authors.lastname: Allgayer
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D008156:Luciferases; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1