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Glypican 3

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GPC3
Identifiers
AliasesGPC3, DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, SGBS1, Glypican 3
External IDsOMIM: 300037; MGI: 104903; HomoloGene: 20944; GeneCards: GPC3; OMA:GPC3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2719

14734

Ensembl

ENSG00000147257

ENSMUSG00000055653

UniProt

P51654

Q8CFZ4

RefSeq (mRNA)

NM_004484
NM_001164617
NM_001164618
NM_001164619

NM_016697

RefSeq (protein)

NP_001158089
NP_001158090
NP_001158091
NP_004475
NP_004475.1

NP_057906

Location (UCSC)Chr X: 133.54 – 133.99 MbChr X: 51.36 – 51.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene.[5][6][7][8] 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.[9] Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).[9]

Structure and function

Schematic of the glypican-3 (GPC3) protein[9]

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.[9] 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.[7] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[10][11] The core protein of GPC3 may serve as a co-receptor or a receiver for Wnt. A cysteine-rich domain at the N-lobe of GPC3 has been identified as a hydrophobic groove that interacts with Wnt3a.[11] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.[11] Wnt also recognizes a heparan sulfate structure on GPC3 , which contains IdoA2S and GlcNS6S, and that the 3-O-sulfation in GlcNS6S3S significantly enhances the binding of Wnt to heparan sulfate.[12]

Disease linkage

Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome.[13]

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[14] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[15] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[16] The YP7 murine antibody has been humanized and named as 'hYP7'.[17] 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.[9] However, the significance of GPC3 as a diagnostic tool for human tumors other than HCC is unclear.

Therapeutic potential

GPC3 is a promising therapeutic target for treating liver cancer.[18] Several therapeutic anti-GPC3 antibodies have been developed, including GC33[19] and YP7.[16][17] The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 and other murine monoclonal antibodies that recognize the C-lobe of GPC3 by hybridoma technology.[16] These antibodies have been humanized (e.g. hYP7) using antibody engineering for clinical applications.[17] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[20] targeting the N-lobe of GPC3 [11] and the human monoclonal antibody HS20[21][22] targeting the heparan sulfate chains on GPC3 by phage display technology. Both HN3 and HS20 antibodies inhibit Wnt signaling in liver cancer cells . The immunotoxins based on HN3,[23][24][25] the antibody-drug conjugates based on hYP7[26] and the T-cell engaging bispecific antibodies derived from YP7[27] and GC33,[28] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33,[29] hYP7[30][31] and HN3[32] are being developed at various stages for treating liver cancer. In mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells can eliminate GPC3-positive cancer cells, by inducing perforin- and granzyme-mediated cell death and reducing Wnt signaling in tumor cells.[31]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000147257 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055653 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, et al. (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.
  6. ^ 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.
  7. ^ a b "Entrez Gene: GPC3 glypican 3".
  8. ^ 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.
  9. ^ a b c d e 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.
  10. ^ 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.
  11. ^ a b c d Li N, Wei L, Liu X, Bai H, Ye Y, Li D, et al. (October 2019). "A Frizzled-Like Cysteine-Rich Domain in Glypican-3 Mediates Wnt Binding and Regulates Hepatocellular Carcinoma Tumor Growth in Mice". Hepatology. 70 (4): 1231–1245. doi:10.1002/hep.30646. PMC 6783318. PMID 30963603.
  12. ^ 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. Bibcode:2016NatSR...626245G. doi:10.1038/srep26245. PMC 4869111. PMID 27185050.
  13. ^ Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, et al. (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.
  14. ^ Filmus J, Capurro M (2004). "Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma". Molecular Diagnosis. 8 (4): 207–12. doi:10.1007/bf03260065. PMID 15887976.
  15. ^ 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.
  16. ^ a b c 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.
  17. ^ a b c Zhang YF, Ho M (September 2016). "Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma". Scientific Reports. 6: 33878. Bibcode:2016NatSR...633878Z. doi:10.1038/srep33878. PMC 5036187. PMID 27667400.
  18. ^ Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, et al. (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.
  19. ^ Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, et al. (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.
  20. ^ Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, et al. (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. Bibcode:2013PNAS..110E1083F. doi:10.1073/pnas.1217868110. PMC 3607002. PMID 23471984.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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. Bibcode:2015NatCo...6.6536G. doi:10.1038/ncomms7536. PMC 4357278. PMID 25758784.
  24. ^ 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.
  25. ^ Fleming BD, Urban DJ, Hall MD, Longerich T, Greten TF, Pastan I, Ho M (May 2020). "Engineered Anti-GPC3 Immunotoxin, HN3-ABD-T20, Produces Regression in Mouse Liver Cancer Xenografts Through Prolonged Serum Retention". Hepatology. 71 (5): 1696–1711. doi:10.1002/hep.30949. PMC 7069773. PMID 31520528.
  26. ^ Fu Y, Urban DJ, Nani RR, Zhang YF, Li N, Fu H, et al. (August 2019). "Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma". Hepatology. 70 (2): 563–576. doi:10.1002/hep.30326. PMC 6482108. PMID 30353932.
  27. ^ "Federal Register /Vol. 82, No. 96 / Friday, May 19, 2017" (PDF).
  28. ^ Ishiguro T, Sano Y, Komatsu SI, Kamata-Sakurai M, Kaneko A, Kinoshita Y, et al. (October 2017). "An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors". Science Translational Medicine. 9 (410): eaal4291. doi:10.1126/scitranslmed.aal4291. PMID 28978751.
  29. ^ Gao H, Li K, Tu H, Pan X, Jiang H, Shi B, et al. (December 2014). "Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma". Clinical Cancer Research. 20 (24): 6418–28. doi:10.1158/1078-0432.CCR-14-1170. PMID 25320357.
  30. ^ Li D, Li N, Zhang Y, Fu H, Torres MB, Wang Q, Greten TF, Ho M (2018-07-01). "Abstract 2549: Development of CAR T-cell therapy targeting glypican-3 in liver cancer". Immunology. American Association for Cancer Research: 2549. doi:10.1158/1538-7445.AM2018-2549.
  31. ^ a b Li D, Li N, Zhang YF, Fu H, Feng M, Schneider D, et al. (February 2020). "Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice". Gastroenterology. 0. doi:10.1053/j.gastro.2020.02.011. PMID 32060001.
  32. ^ Le Trinh T, Wu Q, Chang LJ, Ho M, Liu C (2016-07-15). "Abstract 2316: GPC3-specific chimeric antigen receptor T cell in combination with Sorafenib as a novel therapeutic treatment for hepatocellular carcinoma". Immunology. American Association for Cancer Research: 2316. doi:10.1158/1538-7445.AM2016-2316.

Further reading

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