Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versican generates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhanced cell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis. Futhermore, the V1 isoform was able to not only activate proto-oncogene EGFR expression and modulate its downstream signaling pathway, but also induce p27 degradation and enhance CDK2 kinase activity. As well, the V1 isoform down-regulated the expression of the proapoptotic protein Bad. By contrast, the V2 isoform exhibited opposite biological activities by inhibiting cell proliferation and down-regulated the expression of EGFR and cyclin A. Furthermore, V2 did not contribute apoptotic resistance to the cells. In light of these results, we are reporting opposite functions for the two versican isoforms whose expression is differentially regulated. Our studies suggest that the roles of these two isoforms are associated with the subdomains CS␤ and CS␣, respectively. These results were confirmed by silencing the expression of versican V1 with small interfering RNA (siRNA), which abolished V1-enhanced cell proliferation and V1-induced reduction of apoptosis.

Versican/PG-M is an extracellular matrix proteoglycan, expression of which is elevated in a variety of human tumors. The significance of this change is unclear. Here we show that versican G3-containing fragments are present at high levels in human astrocytoma. Expression of a versican G3 construct in U87 astrocytoma cells enhances colony growth in soft agarose gel and tumor growth and blood vessel formation in nude mice. The G3-containing medium enhances endothelial cell adhesion, proliferation, and migration. G3-expressing cells and tumors formed by these cells express increased levels of fibronectin and vascular endothelial growth factor (VEGF). Furthermore, the G3 domain directly binds to fibronectin and forms a complex together with VEGF. In the presence of these three molecules, endothelial cell adhesion, proliferation, and migration were found to be significantly enhanced. Removal of the complex containing these molecules reverses these processes. Taken together, these findings implicate G3 as a modifier of tumor growth and angiogenesis and suggest a new avenue for development of anticancer and anti-angiogenic therapies based on targeting versican G3 fragments.