Heparan sulfate (HS), a polysaccharide ubiquitously expressed in animals, is essential for development and homeostasis. Degradation of HS by heparanase, an endoglucuronidase, may affect pathophysiological function. Expression of the heparanase gene has been found elevated in a number of pathological conditions. The goal of this work was to investigate the impact of heparanase on expression of other genes. DNA microarray analysis revealed that 1, 042 genes in the cortex and 1,039 genes in the thalamus are up- or down-regulated more than 2-fold in mouse brain overexpresssing human heparanase. Of these genes, two of the early growth response genes, Egr1 and Egr2, are substantially upregulated in the cortex, but essentially unchanged in the thalamus. RT-PCR analysis demonstrated a significant increase of Egr2, but a minor increase of Egr1, in human embryonic kidney cells stably overexpressing heparanase. The upregulated expression of Egr genes is also observed in hepatoma cells with upregulated expression of heparanase. Earlier studies reported that Egr1 induced heparanase expression; our findings suggest a possible reciprocal regulation of Egr and heparanase expression. Furthermore, overexpression of heparanase influenced expression of most genes involved in heparan sulfate proteoglycan biosynthesis, albeit to a different degree in the cortex and thalamus of the transgenic mice.