Post-transcriptional regulation of heparanase gene expression by a 3′ AU-rich element

Heparanaseup-regulation was documented in an increasing number of human carcinomas, associated with poor prognosis. The purpose of the current study was to identify mechanisms responsible for heparanaseinduction. We provide evidence that heparanaseexpression is regulated at the post-transcriptional level by sequences at the 3′ untranslated region(3′ UTR) of the gene. Constructing the 3′ UTR immediately following the heparanasecDNA reduces heparanaseenzymatic activity and protein levels, resulting in decreased cellular invasion capacity. We further identified a 185-bp sequence within the 3′ UTR that mediates heparanasedown-regulation, and characterized an adenine (A)/ uracil(U)-rich consensus element (ARE) within this region. Deletion of the entire 185-bp region or the ARE eliminated the inhibitory effect of the 3′ UTR, resulting in elevated heparanaselevels and formation of larger tumor xenografts indistinguishable from those produced by heparanase-overexpressing cells in terms of size, vasculariz...