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

An imbalance between the activity of matrix metalloproteinases (MMPs) (prot eolytic 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 MIMP-1 messenger R NA (mRNA) levels were observed in malignant cells under basal conditions, i n 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)(C), elicited an increase i n MMP-1 mRNA, with a peak stimulation after a 3- to 4-h culture period. Epi dermal 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 cel ls. In benign cells, however, TPA induced a small, though significant, incr ease 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 mo re extensive extracellular matrix protein breakdown by malignant thyrocytes , as expected of cells exhibiting invasive capacity. TSH (10-500 mu U/mL) f ailed 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 ma lignant cells, and TPA-stimulated MMP-1 and TIMP-1 in benign cells. The rep ressive action of TSH on MMP-1 mRNA was mimicked by forskolin and 8-bromo-c AMP and was abrogated by the PRA inhibitor, H-89, suggesting that the TSH i nhibitory action is PKA-mediated. In conclusion, the present study provides novel data on MMP-1 and TIMP-1 ge ne expression and their modulation by the major signal transduction pathway s operating in human thyroid cells. Similar and divergent patterns have eme rged in the regulation of such gene expression in benign and malignant huma n thyrocytes, in many instances in accord with the concept of MMP playing t he role of stimulating, and TIMP inhibiting, cell invasion. Although MMP-1 maybe just one of the many factors responsible for tumor cell. invasion, th e present findings demonstrating the possibility, at least in vitro, of rep ressing MMP gene expression may have important clinical ramifications.