For detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis, serum ␣-fetoprotein has been widely used, but its sensitivity has not been satisfactory, especially in small, well-differentiated HCC, and complementary serum marker has been clinically required. Glypican-3 (GPC3), a heparan sulfate proteoglycan anchored to the plasma membrane, is a good candidate marker of HCC because it is an oncofetal protein overexpressed in HCC at both the mRNA and protein levels. In this study, we demonstrated that its NH 2 -terminal portion [soluble GPC3 (sGPC3)] is cleaved between Arg 358 and Ser 359 of GPC3 and that sGPC3 can be specifically detected in the sera of patients with HCC. Serum levels of sGPC3 were 4.84 ؎ 8.91 ng/ml in HCC, significantly higher than the levels seen in liver cirrhosis (1.09 ؎ 0.74 ng/ml; P < 0.01) and healthy controls (0.65 ؎ 0.32 ng/ml; P < 0.001). In well-or moderately-differentiated HCC, sGPC3 was superior to ␣-fetoprotein in sensitivity, and a combination measurement of both markers improved overall sensitivity from 50% to 72%. These results indicate that sGPC3 is a novel serological marker essential for the early detection of HCC.

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Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis.