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Identification of Soluble NH₂-Terminal Fragment of Glypican-3 as a Serological Marker for Early-Stage Hepatocellular Carcinoma

¹ Genome Science Division, ² Division of Dynamical Bioinformatics, and ³ Division of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Departments of ⁴ Gastroenterology and ⁵ Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; ⁶ Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; and ⁷ Perseus Proteomics, Inc., Tokyo, Japan

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 NH₂-terminal portion [soluble GPC3 (sGPC3)] is cleaved between Arg³⁵⁸ and Ser³⁵⁹ 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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