Transforming growth factor beta 1 regulation of metalloproteinase production in cultured human cervical epithelial cells

Collagenase levels are regulated in a cell type-specific manner by a variety of growth factors and cytokines, and increased type IV collagenase activity in tumor cells has been linked to metastatic growth. In this study we compare the effects of epidermal growth factor (EGF) and transforming growth factor beta 1 (TGF beta 1) on gelatinase production in cervical epithelial cell lines. EGF is a strong mitogen for cervical epithelial cells and TGF beta 1 suppresses growth. Metalloproteinase zymograms of conditioned medium from normal human ectocervical cells reveal two major bands of metalloproteinase activity at 72 and 92 Kd. In contrast, the level of the 92-Kd activity is greatly reduced in the human papillomavirus type 16-positive ECE16-1 and CaSki cells. EGF treatment produces minimal changes in metalloproteinase levels. Treatment of CaSki cells with 20 ng/ml of EGF reduces by 30 to 50% the level of both activities. In ECE16-1 cells, EGF decreases the 72-Kd activity by 50% and the 92-Kd activity slightly. TGF beta 1 treatment, in contrast, increases the 72-Kd activity 3- to 10-fold and the 92-Kd activity by > or = 25-fold in each cell type. In CaSki and ECE16-1 cells, the changes in metalloproteinase level are mediated by changes in level of the corresponding mRNAs. In each case, the metalloproteinases are secreted as inactive proenzymes which can be activated by in vitro treatment with organomercurials. Tests of a series of additional cervical cell lines reveal that metalloproteinase levels are generally higher in normal cervical cells and in cells immortalized by transfection with HPV16, whereas lower levels are observed in cells derived from human tumors. Moreover, a higher percentage of cell lines derived from human tumors do not respond to TGF beta 1 regulation of metalloproteinase levels. Parallel studies indicate that the TGF beta 1-stimulated increase in the 72- and 92-Kd activities is correlated with enhanced chemotactic and chemoinvasive behavior in both ECE16-1 and CaSki cells.