Glypican-3 is a protein that in humans is encoded by the GPC3gene.[1][2][3][4] The GPC3 gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 amino acids.[5] Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).[5]
The protein core of GPC3 consists of two subunits, where the N-terminal subunit has a size of ~40 kDa and the C-terminal subunit is ~30 kDa.[5] Six glypicans (GPC1-6) have been identified in mammals. Cell surface heparan sulfateproteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosylphosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.[3] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[6] A biochemical study has revealed that Wnt recognizes a heparan sulfate structure on GPC3 containing IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to the glypican.[7]
Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhoticlivers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[9] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in cholangiocarcinoma.[10] The YP7 murine antibody has been humanized and named as 'hYP7'. [11] GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors.[5] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.
Therapeutic potential
Glypican 3 is a potential therapeutic target for treating liver cancer and other cancers.[5][6] Several therapeutic anti-GPC3 antibodies have been developed. Humanized monoclonal antibodies (GC33,[12] hYP7[10] ) recognize the C-lobe of GPC3. The laboratory of Dr. Mitchell Ho at the National Cancer Institute reported the human single-domain antibody HN3[13] targeting the N-lobe of GPC3 and the human monoclonal antibody HS20[14][15] targeting the heparan sulfate chains of GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3 [16][17] and antibody-drug conjugates based on hYP7 [18] have been developed for treating liver cancer.
↑Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D (March 1996). "Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome". Nature Genetics. 12 (3): 241–7. doi:10.1038/ng0396-241. PMID8589713.
↑Veugelers M, Vermeesch J, Watanabe K, Yamaguchi Y, Marynen P, David G (October 1998). "GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome". Genomics. 53 (1): 1–11. doi:10.1006/geno.1998.5465. PMID9787072.
↑Jakubovic BD, Jothy S (April 2007). "Glypican-3: from the mutations of Simpson-Golabi-Behmel genetic syndrome to a tumor marker for hepatocellular carcinoma". Experimental and Molecular Pathology. 82 (2): 184–9. doi:10.1016/j.yexmp.2006.10.010. PMID17258707.
↑Davoodi J, Kelly J, Gendron NH, MacKenzie AE (June 2007). "The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26". Proteomics. 7 (13): 2300–10. doi:10.1002/pmic.200600654. PMID17549790.
↑Anatelli F, Chuang ST, Yang XJ, Wang HL (August 2008). "Value of glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy". American Journal of Clinical Pathology. 130 (2): 219–23. doi:10.1309/WMB5PX57Y4P8QCTY. PMID18628090.
↑Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, Sugo I, Ohizumi I, Aburatani H, Hamakubo T, Kodama T, Tsuchiya M, Yamada-Okabe H (December 2008). "Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer". Cancer Research. 68 (23): 9832–8. doi:10.1158/0008-5472.CAN-08-1973. PMID19047163.
↑Fu Y, Urban DJ, Nani RR, Zhang YF, Li N, Fu H, Shah H, Gorka AP, Guha R, Chen L, Hall MD, Schnermann MJ, Ho M (October 2018). "Glypican-3 Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma". Hepatology. doi:10.1002/hep.30326. PMID30353932.
Further reading
Li M, Squire JA, Weksberg R (March 1998). "Overgrowth syndromes and genomic imprinting: from mouse to man". Clinical Genetics. 53 (3): 165–70. doi:10.1111/j.1399-0004.1998.tb02668.x. PMID9630066.
Xuan JY, Besner A, Ireland M, Hughes-Benzie RM, MacKenzie AE (January 1994). "Mapping of Simpson-Golabi-Behmel syndrome to Xq25-q27". Human Molecular Genetics. 3 (1): 133–7. doi:10.1093/hmg/3.1.133. PMID7909248.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Shen T, Sonoda G, Hamid J, Li M, Filmus J, Buick RN, Testa JR (January 1997). "Mapping of the Simpson-Golabi-Behmel overgrowth syndrome gene (GPC3) to chromosome X in human and rat by fluorescence in situ hybridization". Mammalian Genome. 8 (1): 72. doi:10.1007/s003359900357. PMID9021160.
Lage H, Dietel M (April 1997). "Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5". Gene. 188 (2): 151–6. doi:10.1016/S0378-1119(96)00689-0. PMID9133586.
Huber R, Crisponi L, Mazzarella R, Chen CN, Su Y, Shizuya H, Chen EY, Cao A, Pilia G (October 1997). "Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene". Genomics. 45 (1): 48–58. doi:10.1006/geno.1997.4916. PMID9339360.
Hsu HC, Cheng W, Lai PL (November 1997). "Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution". Cancer Research. 57 (22): 5179–84. PMID9371521.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A (December 1998). "Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome". Developmental Dynamics. 213 (4): 431–9. doi:10.1002/(SICI)1097-0177(199812)213:4<431::AID-AJA8>3.0.CO;2-7. PMID9853964.
Veugelers M, Cat BD, Muyldermans SY, Reekmans G, Delande N, Frints S, Legius E, Fryns JP, Schrander-Stumpel C, Weidle B, Magdalena N, David G (May 2000). "Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene". Human Molecular Genetics. 9 (9): 1321–8. doi:10.1093/hmg/9.9.1321. PMID10814714.
Khan S, Blackburn M, Mao DL, Huber R, Schlessinger D, Fant M (January 2001). "Glypican-3 (GPC3) expression in human placenta: localization to the differentiated syncytiotrophoblast". Histology and Histopathology. 16 (1): 71–8. doi:10.14670/HH-16.71. PMID11193214.