Heparan sulfate proteoglycans and their modification as promising anticancer targets in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer. Despite advancements in the treatment strategies of HCC, there is an urgent requirement to identify and develop novel therapeutic drugs that do not lead to resistance. These novel agents should have the potential to influence the primary mechanisms participating in the pathogenesis of HCC. Heparan sulfate proteoglycans (HSPGs) are major elements of the extracellular matrix that perform structural and signaling functions. HSPGs protect against invasion of tumor cells by preventing cell infiltration and intercellular adhesion. Several enzymes, such as heparanase, matrix metalloproteinase-9 and sulfatase-2, have been reported to affect HSPGs, leading to their degradation and thus enhancing tumor invasion. In addition, some compounds that are produced from the degradation of HSPGs, including glypican-3 and syndecan-1, enhance tumor progression. Thus, the identification of enzymes that affect HSPGs or their degradation products in HCC may lead to the development of novel therapeutic targets. The present review discusses the main enzymes and compounds associated with HSPGs, and their involvement with the pathogenicity of HCC.

Keywords: fascin; glypican-3; heparanase; matrix metalloproteinase-9; sulfatase-2; syndecan-1.

Figure 1.

HSPGs pathway changes in HCC. HCC increases the ability of the enzymes, MMP-9, sulfatase-2 and heparanase to attack HPSGs, leading to the formation of several intermediate compounds that enhance inflammation and tumor invasion. HSPGs, heparan sulfate proteoglycans; HCC, hepatocellular carcinoma; MMP, matrix metalloproteinase; FGF, fibroblast growth factor; E-cad, E-cadherin; Synd-1, syndecan-1; IGF, insulin-like growth factor; GPC3, glypcian-3; PKC, protein kinase C; NFκB, nuclear factor κB; TNF-α, tumor necrosis factor-α.