Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play an important role in tumor invasion and metastasis. There have been only a few studies on the protein expression of MMPs and TIMPs in thyroid carcinomas. Therefore, we investigated the protein expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 in 86 papillary thyroid carcinomas using immunohistochemistry, semiquantitative scoring morphometry of immunohistochemistry, gelatin zymography, and western blotting. We also examined the correlations between the immunohistochemical scores and several clinicopathological parameters. The immunoreactivities of MMP-2, MMP-9, TIMP-1, and TIMP-2 were largely located in the tumor cells or non-tumor follicular cells and to a much lesser extent in the fibroblasts and endothelial cells in the tumor and non-tumor regions. Compared with non-tumor regions, these four proteins tended to be overexpressed in the tumor cells; the overexpression was found in 64 of 86 (74%), 80 of 86 (93%), 79 of 86 (92%), and 64 of 86 (74%) cases for MMP-2, MMP-9, TIMP-1, and TIMP-2, respectively. Gelatin zymography showed distinct bands of MMP-2 and MMP-9 in tumor extracts but vague bands in non-tumor extracts. Western blotting revealed the specific bands of MMP-2 and MMP-9 in both tumor and non-tumor extracts. Morphometric scoring revealed that high expression of these proteins significantly correlated with large tumor size, presence of lymph node metastasis, high clinical stage, high intrathyroidal invasion, and high vascular invasion. These data suggest that MMP-2, MMP-9, TIMP-1, and TIMP-2 proteins and activities are increased in tumors cells of papillary thyroid carcinomas and that they play an important role in the invasion and metastasis of papillary thyroid carcinomas.

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

“…Expression of MMP-2 and MMP-9 is elevated in carcinomas in association with low differentiation grade and accelerated tumour progression in oral carcinoma, 30 lung adenocarcinoma, 31 bladder 32 and ovarian carcinoma 33 and papillary thyroid carcinoma. 34 MMP-2 expression correlates also with advanced disease in neuroblastoma. 35 MMP-2 36,37 or MT1-MMP are not expressed in cervical neoplasia but their expression levels are high in cervical carcinoma and correlate with advanced stage.…”

“…47 Invasive behavior of gastric carcinoma is associated with MT1-MMP expression 48 and bladder carcinoma with both MMP-2 and MT1-MMP expression. 49 In papillary thyroid carcinoma, high MMP-2 and MMP-9 expression 34 Recent observations show that insertion of G nucleotide at Ϫ1607 bp in MMP-1 promoter generates a new ETS binding site and increases the transcription of the MMP-1 gene. 50 Homozygosity for this single nucleotide insertion polymorphism (2G allele) has been shown to correlate with invasiveness of colorectal cancer 51 and cutaneous melanoma.…”

Cancer Preventive Mechanismsof the Green Tea Polyphenol (-)-Epigallocatechin-3-gallate

“…A large body of experimental evidence suggested that MMPs essentially contributed to the maintenance of tumor growth in primary and metastatic sites [55][56][57]. Adhami et al [58] have shown that p.o.…”

Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion

“…Although some correlation studies support an association between specific genetic alterations and aggressive cancer behavior (6)(7)(8)(9), there are a number of events that are found nearly exclusively in aggressive PTCs, including mutations of P53 (10,11), dysregulated ␤-catenin signaling (12), up-regulation of cyclin D1 (13), and overexpression of metastasis-promoting, angiogenic, and/or cell adhesion-related genes (14)(15)(16)(17)(18)(19)(20). We have determined that invasive regions of primary PTCs are frequently characterized by enhanced Akt activity and cytosolic p27 localization (21,22).…”