Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis.

Abstract

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-alpha (PDGFRalpha). 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(Waf) (1/) (Cip) (1) and concurrent activation (phosphorylation) of PDGFRalpha in the hepatocellular carcinomas generated in the decorin-null vis-a-vis wild-type mice. Notably, in normal liver PDGFRalpha localized primarily to the membrane of nonparenchymal cells, whereas in the malignant counterpart PDGFRalpha 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 PDGFRalpha, and could be a novel therapeutic agent in the battle against liver cancer.