Membrane-type 1 matrix metalloproteinase mediated progelatinase A activation in non-tumorigenic and tumorigenic human keratinocytes

Elevated expression of type IV collagenases (MMP-2 and MMP-9) has been stro ngly correlated with tumour progression and metastasis in various tumours. Here, we analysed expression and activation of these MMPs in non-tumourigen ic HaCaT cells and the malignant HaCaT variant II-4(rt). In monolayer cultu res, both cell types secreted latent MMP-2 (proMMP-2) in comparable amounts , while MMP-9 production was clearly higher in II-4(rt) cells. Upon contact with fibrillar collagen type I the malignant II-4(rt) cells, but not the H aCaT cells, gained the capability to activate proMMP-2. This process is sho wn to be membrane-associated and mediated by MT1-MMP. Surprisingly, all mem brane preparations from either HaCaT cells or II-4(rt) cells grown as monol ayers, as well as within collagen gels, contained considerable amounts of a ctive MT1-MMP. However, within collagen gels HaCaT cells showed significant ly higher TIMP-2 levels compared to II-4(rt) cells. This indicates that TIM P-2 might play a central role for MT1-MMP-mediated gelatinolytic activity. Indeed, collagen type I-induced MT1-MMP-mediated proMMP-2 activation by II- 4(rt) membranes could be completely abolished by an excess of TIMP-2. In co nclusion, our data suggest that MT1-MMP-mediated proMMP4 activation might b e associated with malignant progression of epidermal tumour cells. (C) 2000 Cancer Research Campaign.