Buergy Daniel, Weber Theresia, Maurer Gabriele D, Mudduluru Giridhar, Medved Fabian, Leupold Joerg H, Brauckhoff Michael, Post Stefan, Dralle Henning, Allgayer Heike
Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Mannheim Faculty, University of Heidelberg, and DKFZ Heidelberg, Mannheim, Germany.
Int J Cancer. 2009 Aug 15;125(4):894-901. doi: 10.1002/ijc.24462.
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.
甲状腺癌高危患者的识别以及滤泡性腺瘤与癌的术前鉴别在临床上仍然具有挑战性。我们开展这项研究是为了分析基质金属蛋白酶（MMPs）和尿激酶型纤溶酶原激活物受体（u-PAR）的定量以及与u-PAR启动子结合的转录因子是否能提高甲状腺肿瘤的预后预测能力和鉴别诊断能力。从69例接受前瞻性随访的甲状腺癌（乳头状癌、髓样癌、滤泡状癌和未分化癌，即PTC、MTC、FTC和ATC）或滤泡性腺瘤患者中收集肿瘤组织/正常组织。通过酶联免疫吸附测定法（ELISA）测定u-PAR、MMP-1、MMP-7和MMP-9的含量，并通过电泳迁移率变动分析测定转录因子结合情况。观察到转录因子与u-PAR启动子的结合，但与u-PAR表达无关。除MTC外，癌组织中u-PAR/MMPs的表达明显高于腺瘤/正常组织，这与晚期pT分期或M分期相关。滤泡状癌中MMP-1和MMP-9明显高于腺瘤。在癌组织中，高u-PAR基因表达与高MMP-9显著相关，后者在正常组织中与MMP-7相关。分化型肿瘤患者的不良生存呈趋势性相关（p = 0.07）；所有患者（p = 0.043）尤其是滤泡起源癌（包括ATC）患者而非髓样癌患者的不良生存与高u-PAR蛋白显著相关（p = 0.015）。u-PAR的定量在非C细胞起源的甲状腺癌中具有预后意义，并且u-PAR在甲状腺癌中部分可能受非转录调控。这是第一项提示MMP-1/-9作为滤泡性腺瘤和滤泡状癌之间重要鉴别标志物的研究。
