Document Detail

Similar and divergent patterns in the regulation of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1 gene expression in benign and malignant human thyroid cells.
MedLine Citation:
PMID:  10487706     Owner:  NLM     Status:  MEDLINE    
An imbalance between the activity of matrix metalloproteinases (MMPs) (proteolytic enzymes that degrade protein components of the extracellular matrix) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), may be one of the mechanisms responsible for tumor cell invasion. We have investigated the regulation of MMP-1 and TIMP-1 gene expression in benign and malignant (follicular, anaplastic, and papillary) human thyroid cells. As expected of cells with invasive potential, detectable MMP-1 messenger RNA (mRNA) levels were observed in malignant cells under basal conditions, in contrast to undetectable levels in benign cells. Exposure of these cells, for 1 h, to the active phorbol ester, phorbol 12-myristate 13-acetate (TPA, 100 nmol/L), acting via protein kinase C (PKC), elicited an increase in MMP-1 mRNA, with a peak stimulation after a 3- to 4-h culture period. Epidermal growth factor (EGF, 25 ng/mL), however, acting via protein tyrosine kinase (PTK), stimulated such gene expression in malignant cells but failed to do so in benign cells. TIMP-1 mRNA was not significantly altered by the TPA-PKC, EGF-PTK, or TSH-protein kinase A (PKA) pathways in malignant cells. In benign cells, however, TPA induced a small, though significant, increase in TIMP-1. The MMP-1 stimulation by EGF and lack of TPA-induced rise in TIMP-1 in malignant cells, in sharp contrast to the effects obtained in benign thyrocytes, seems to indicate that the MMP: TIMP balance favors a more extensive extracellular matrix protein breakdown by malignant thyrocytes, as expected of cells exhibiting invasive capacity. TSH (10-500 microU/mL) failed to significantly influence basal MMP-1 or TIMP-1 mRNA levels, but it caused a dose-dependent inhibition in TPA- and EGF-induced MMP-1 mRNA in malignant cells, and TPA-stimulated MMP-1 and TIMP-1 in benign cells. The repressive action of TSH on MMP-1 mRNA was mimicked by forskolin and 8-bromo-cAMP and was abrogated by the PKA inhibitor, H-89, suggesting that the TSH inhibitory action is PKA-mediated. In conclusion, the present study provides novel data on MMP-1 and TIMP-1 gene expression and their modulation by the major signal transduction pathways operating in human thyroid cells. Similar and divergent patterns have emerged in the regulation of such gene expression in benign and malignant human thyrocytes, in many instances in accord with the concept of MMP playing the role of stimulating, and TIMP inhibiting, cell invasion. Although MMP-1 may be just one of the many factors responsible for tumor cell invasion, the present findings demonstrating the possibility, at least in vitro, of repressing MMP gene expression may have important clinical ramifications.
S Korem; M B Resnick; Z Kraiem
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  84     ISSN:  0021-972X     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  1999 Sep 
Date Detail:
Created Date:  1999-10-06     Completed Date:  1999-10-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3322-7     Citation Subset:  AIM; IM    
Endocrine Research Unit, Carmel Medical Center, Haifa, Israel.
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MeSH Terms
8-Bromo Cyclic Adenosine Monophosphate / pharmacology
Adenocarcinoma, Follicular / enzymology
Carcinoma / enzymology
Carcinoma, Papillary / enzymology
Cells, Cultured
Collagenases / genetics*
Cyclic AMP-Dependent Protein Kinases / metabolism
Epidermal Growth Factor / pharmacology
Forskolin / pharmacology
Gene Expression Regulation, Enzymologic*
Matrix Metalloproteinase 1
Protein Kinase C / metabolism
Protein-Tyrosine Kinases / metabolism
RNA, Messenger / analysis
Tetradecanoylphorbol Acetate / pharmacology
Thyroid Neoplasms / enzymology*
Thyrotropin / pharmacology
Tissue Inhibitor of Metalloproteinase-1 / genetics*
Reg. No./Substance:
0/RNA, Messenger; 0/Tissue Inhibitor of Metalloproteinase-1; 16561-29-8/Tetradecanoylphorbol Acetate; 23583-48-4/8-Bromo Cyclic Adenosine Monophosphate; 62229-50-9/Epidermal Growth Factor; 66428-89-5/Forskolin; 9002-71-5/Thyrotropin; EC Kinases; EC AMP-Dependent Protein Kinases; EC Kinase C; EC 3.4.24.-/Collagenases; EC Metalloproteinase 1

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