Differential regulation of protease and extracellular matrix protein expression by transforming growth factor-beta 1 in non-small cell lung cancer cells and normal human bronchial epithelial cells

Abstract

In addition to autoregulating its own expression, transforming growth factor-beta 1 (TGF- β1) also regulates the production of proteases, protease inhibitors and extracellular matrix proteins. To investigate the relationship between plasminogen activator (PA), plasminogen activator inhibitor-1 (PAI-1) and the extracellular matrix in malignant and normal lung epithelial cells and to determine whether malignant lung epithelial cells may be more invasive than normal lung epithelial cells because of differences in expression of these proteins in response to TGF- β, the regulation of PA, PAI-1, fibronectin, laminin and thrombospondin by TGF- β1 in human non-small cell lung cancer (NSCLC) cells was examined and compared with normal human bronchial epithelial (NHBE) cells. TGF- β1 caused a persistent increase in expression of the mRNAs for both PA and PAI-1 in NSCLC cells, with the increase in PAI-1 mRNA beginning several hours before that of PA mRNA. By immunoprecipitation analysis, it was shown that TGF- β1 also induced a corresponding increase in the amount of PAI-1 protein in these NSCLC cells as well. In contrast, while TGF- β1 also increased expression of PAI-1 mRNA in NHBE cells, expression of PA mRNA decreased simultaneously. Treatment of NSCLC cells with TGF- β1 resulted in a persistent increase in expression of the mRNAs for fibronectin, laminin and thrombospondin; expression of fibronectin protein also increased after treatment with TGF- β1 in these cells. When NHBE cells were similarly cultured in the presence of TGF- β1, expression of fibronectin mRNA also increased in a persistent manner; however, only an early transient increase in the level of the mRNAs for laminin and thrombospondin was detected in these cells. These data show that there is differential regulation of the genes for PA and PAI-1 and the extracellular matrix protein fibronectin in response to TGF- β1 not only when NSCLC and NHBE cells are compared, but also when different NSCLC cells are compared with each other.