Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma.
For detection of hepatocellular carcinoma (HCC) in patients with liver cirrhosis, serum alpha-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 alpha-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.
Hippo
Yoshitaka
Y
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Watanabe
Kiyotaka
K
Watanabe
Akira
A
Midorikawa
Yutaka
Y
Yamamoto
Shogo
S
Ihara
Sigeo
S
Tokita
Susumu
S
Iwanari
Hiroko
H
Ito
Yukio
Y
Nakano
Kiyotaka
K
Nezu
Jun-ichi
J
Tsunoda
Hiroyuki
H
Yoshino
Takeshi
T
Ohizumi
Iwao
I
Tsuchiya
Masayuki
M
Ohnishi
Shin
S
Makuuchi
Masatoshi
M
Hamakubo
Takao
T
Kodama
Tatsuhiko
T
Aburatani
Hiroyuki
H
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D014408:Biomarkers, Tumor / Q000097:blood* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D053673:Glypicans; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000097:blood*; D008565:Membrane Proteins / Q000097:blood* / Q000737:chemistry / Q000276:immunology; D009363:Neoplasm Proteins / Q000097:blood* / Q000737:chemistry / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry; D012680:Sensitivity and Specificity; D012995:Solubility
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; C105937:GPC3 protein, human; D053673:Glypicans; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments