Down-regulation of MT1-MMP expression by the alpha 3 chain of type IV collagen inhibits bronchial tumor cell line invasion

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surro unded by a remnant or neosynthetized BM material. We have previously report ed the presence of a particular a chain of type IV collagen, the alpha3(IV) chain, in bronchopulmonary carcinomas. This chain was not detected in the normal bronchial epithelium, but was found around some invasive tumor clust er BM. In the present study, we examined the effects of the alpha3(IV) chai n on the invasive properties of bronchial tumor cell lines, with special em phasis on their expression of matrix metalloproteinase-2 (MMP-2) and its ac tivator, membrane type 1-matrix metalloproteinase (MT1-MMP), which is large ly involved in tumor progression. Two epithelial bronchial cell lines (16HB E14o- and BZR), showing different invasive abilities, were evaluated. Using the Boyden chamber invasion assay, we demonstrated that the alpha3(IV) cha in inhibits the invasive properties of BZR cells and modifies their morphol ogy by inducing an epithelial cell shape. In the presence of the recombinan t NC1 domain of the alpha3(IV) chain, the expression of MMP-2 and tissue in hibitor of metalloproteinase-2 (TIMP-2) was not modified in either cell lin e. The NC1 alpha3(IV) domain did not modulate the MT1-MMP expression of non invasive 16HBE14o-cells, whereas a 50% decrease of MT1-MMP mRNA was observe d in invasive BZR cells. Accordingly, Western blot analyses showed a disapp earance of the 45-kd MT1-MMP form when BZR cells were treated with the reco mbinant NCI alpha3(IV) domain. These findings suggest that the alpha3 chain of type IV collagen may play a role in tumor invasion, at least by decreas ing the expression and synthesis of MT1-MMP.