Converging signals synergistically activate the LAMC2 promoter and lead to accumulation of the laminin gamma 2 chain in human colon carcinoma cells.

The trimeric extracellular matrix molecule laminin-5 and its constituent chains (alpha3, beta3, gamma2) are normally not detectable intracellularly in intestinal epithelial cells but the laminin gamma2 chain can be detected in cancer cells at the invasive front of a subset of colon carcinomas. These cells are subjected to cytokines such as transforming growth factor beta1 (TGF-beta1) and hepatocyte growth factor (HGF), produced by the tumour cells or by the surrounding stromal cells. The purpose of the present work was to investigate whether TGF-beta1 and HGF, known to stimulate the LAMC2 gene encoding the laminin gamma2 chain, might synergize to activate the LAMC2 promoter, and to identify the promoter elements involved. We find evidence for synergy between TGF-beta and HGF with respect to laminin gamma2 chain expression and promoter activation and demonstrate that this requires the 5' activator protein-1 (AP-1) element of the promoter and an additional upstream element which is also responsive to coexpression of the Smad3 protein from the TGF-beta signalling pathway. The transcripts encoding the other laminin-5 chains are not synergistically activated by HGF and TGF-beta. Thus the synergistic activation of the LAMC2 gene is mediated via different cis-elements and results in an overproduction of the laminin gamma2 chain relative to the other laminin-5 constituent chains. This difference may explain why laminin gamma2 chains accumulate in the cells at the invasive front of colon carcinomas.