Decorin, a secreted
small leucine-rich proteoglycan, acts as a
tumor repressor in a variety of
cancers, mainly by blocking the action of several
receptor tyrosine kinases such as the receptors for hepatocyte, epidermal and
insulin-like growth factors. In the present study we investigated the effects of
decorin in an experimental model of
thioacetamide-induced hepatocarcinogenesis and its potential role in modulating the signaling of
platelet-derived growth factor receptor-α (PDGFRα). Genetic ablation of
decorin in mice led to enhanced
tumor prevalence and a higher
tumor count compared with wild-type mice. These findings correlated with decreased levels of the
cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and concurrent activation (phosphorylation) of PDGFRα in the
hepatocellular carcinomas generated in the
decorin-null vis-à-vis wild-type mice. Notably, in normal liver PDGFRα localized primarily to the membrane of nonparenchymal cells, whereas in the malignant counterpart PDGFRα was expressed by the malignant cells at their cell surfaces. This process was facilitated by a genetic background lacking endogenous
decorin. Double immunostaining of the
proteoglycan and the receptor revealed only minor colocalization, leading to the hypothesis that
decorin would bind to the natural
ligand PDGF rather than to the receptor itself. Indeed, we found, using purified
proteins and immune-blot assays, that
decorin binds to PDGF. Collectively, our findings support the idea that
decorin acts as a secreted
tumor repressor during hepatocarcinogenesis by hindering the action of another
receptor tyrosine kinase, such as the PDGFRα, and could be a novel therapeutic agent in the battle against
liver cancer.