Developer site: The content shown here is test data.

MyEClinic
MyEClinic
Health Dictionary AI Health Chat Find an Online Doctor
A serene Zen garden with raked sand and smooth stones, symbolising clarity and calm

Health Dictionary

Reliable, easy-to-read patient information on common medical conditions — written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

Back to skin conditions

Glypican 3

Introduction

Glypican-3 is a protein that in humans is encoded by the GPC3 gene.[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]

Structure and function

Structure and function

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 sulfate proteoglycans 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 glycosyl phosphatidylinositol 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]

Disease linkage

Disease linkage

Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[8]

Diagnostic utility

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) and dysplastic changes in cirrhotic livers; 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

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.

See also

See also

References

References

  1. ↑ 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. PMID 8589713.
  2. ↑ 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. PMID 9787072.
  3. ↑ 3.0 3.1 “Entrez Gene: GPC3 glypican 3”.
  4. ↑ 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. PMID 17258707.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Ho M, Kim H (February 2011). “Glypican-3: a new target for cancer immunotherapy”. European Journal of Cancer. 47 (3): 333–8. doi:10.1016/j.ejca.2010.10.024. PMC 3031711. PMID 21112773.
  6. ↑ 6.0 6.1 Li N, Gao W, Zhang YF, Ho M (November 2018). “Glypicans as Cancer Therapeutic Targets”. Trends in Cancer. 4 (11): 741–754. doi:10.1016/j.trecan.2018.09.004. PMC 6209326. PMID 30352677.
  7. ↑ Gao W, Xu Y, Liu J, Ho M (May 2016). “Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate”. Scientific Reports. 6: 26245. doi:10.1038/srep26245. PMC 4869111. PMID 27185050.
  8. ↑ 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. PMID 17549790.
  9. ↑ 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. PMID 18628090.
  10. ↑ 10.0 10.1 Phung Y, Gao W, Man YG, Nagata S, Ho M (September 2012). “High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening”. mAbs. 4 (5): 592–9. doi:10.4161/mabs.20933. PMC 3499300. PMID 22820551.
  11. ↑ Zhang, Yi-Fan; Ho, Mitchell (2016-09-26). “Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma”. Scientific Reports. 6: 33878. doi:10.1038/srep33878. ISSN 2045-2322. PMC 5036187. PMID 27667400.
  12. ↑ 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. PMID 19047163.
  13. ↑ Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M (March 2013). “Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma”. Proceedings of the National Academy of Sciences of the United States of America. 110 (12): E1083–91. doi:10.1073/pnas.1217868110. PMC 3607002. PMID 23471984.
  14. ↑ Gao W, Kim H, Feng M, Phung Y, Xavier CP, Rubin JS, Ho M (August 2014). “Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy”. Hepatology. 60 (2): 576–87. doi:10.1002/hep.26996. PMC 4083010. PMID 24492943.
  15. ↑ Kim H, Ho M (November 2018). “Isolation of Antibodies to Heparan Sulfate on Glypicans by Phage Display”. Current Protocols in Protein Science. 94 (1): e66. doi:10.1002/cpps.66. PMC 6205898. PMID 30091851.
  16. ↑ Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M (March 2015). “Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis”. Nature Communications. 6: 6536. doi:10.1038/ncomms7536. PMC 4357278. PMID 25758784.
  17. ↑ Wang C, Gao W, Feng M, Pastan I, Ho M (May 2017). “Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy”. Oncotarget. 8 (20): 32450–32460. doi:10.18632/oncotarget.10592. PMC 5464801. PMID 27419635.
  18. ↑ 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. PMID 30353932.
Further reading

Further reading

External links