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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

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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 has been found to regulate Wnt/β-catenin and Yap signaling pathways.[9][10][11][12][13][14][15][16] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[11][17] 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.[17] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.[17] 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.[10] GPC3 also modulates Yap signaling.[12] It interacts with FAT1, a potential upstream cell surface receptor of YAP1 in human cells.[15] GPC3 is also found to bind Alpha-fetoprotein in liver cancer.[18]

Disease linkage

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Deletion mutations in this gene are associated with Simpson–Golabi–Behmel syndrome.[5]

Diagnostic utility

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Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[19] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[20] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[21] The YP7 murine antibody has been humanized and named as 'hYP7'.[22] 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.[9]

Therapeutic potential

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To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33,[23] YP7,[21] HN3[12] and HS20[13][24] have been made and widely tested. The laboratory of Dr. Mitchell Ho at the National Cancer Institute, NIH (Bethesda, Maryland, US) has generated YP7 murine monoclonal antibody that recognizes the C-lobe of GPC3 by hybridoma technology.[21] The antibody has been humanized (named hYP7) via antibody engineering for clinical applications.[22] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[12] targeting the N-lobe of GPC3 [17] and the human monoclonal antibody HS20[13][24] 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,[14][25][26] the antibody-drug conjugates based on hYP7[27] and the T-cell engaging bispecific antibodies derived from YP7[28][29] and GC33,[30] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33,[31] hYP7[32][33] and HN3[34] are being reported 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.[33] CAR (hYP7) T cells are being evaluated at a clinical trial at the NIH.[35]

See also

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References

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  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. ^ a b 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): 241–247. doi:10.1038/ng0396-241. PMID 8589713. S2CID 38846721.
  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): 184–189. doi:10.1016/j.yexmp.2006.10.010. PMID 17258707.
  9. ^ a b c d e f g Ho M, Kim H (February 2011). "Glypican-3: a new target for cancer immunotherapy". European Journal of Cancer. 47 (3): 333–338. doi:10.1016/j.ejca.2010.10.024. PMC 3031711. PMID 21112773.
  10. ^ a b 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.
  11. ^ a b 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.
  12. ^ a b c d 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–E1091. Bibcode:2013PNAS..110E1083F. doi:10.1073/pnas.1217868110. PMC 3607002. PMID 23471984.
  13. ^ a b c 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): 576–587. doi:10.1002/hep.26996. PMC 4083010. PMID 24492943.
  14. ^ a b 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.
  15. ^ a b Meng P, Zhang YF, Zhang W, Chen X, Xu T, Hu S, et al. (January 2021). "Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells". Scientific Reports. 11 (1): 40. doi:10.1038/s41598-020-79524-3. PMC 7794441. PMID 33420124.
  16. ^ Kolluri A, Ho M (2019). "The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer". Frontiers in Oncology. 9: 708. doi:10.3389/fonc.2019.00708. PMC 6688162. PMID 31428581.
  17. ^ 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.
  18. ^ Zhang YF, Lin S, Xiao Z, Ho M (October 2024). "A proteomic atlas of glypican-3 interacting partners: Identification of alpha-fetoprotein and other extracellular proteins as potential immunotherapy targets in liver cancer". Proteoglycan Research. 2 (4). doi:10.1002/pgr2.70004. ISSN 2832-3556.
  19. ^ Filmus J, Capurro M (2004). "Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma". Molecular Diagnosis. 8 (4): 207–212. doi:10.1007/bf03260065. PMID 15887976. S2CID 6312940.
  20. ^ 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): 219–223. doi:10.1309/WMB5PX57Y4P8QCTY. PMID 18628090. S2CID 45888415.
  21. ^ 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): 592–599. doi:10.4161/mabs.20933. PMC 3499300. PMID 22820551.
  22. ^ a b 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.
  23. ^ 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): 9832–9838. doi:10.1158/0008-5472.CAN-08-1973. PMID 19047163.
  24. ^ a b 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ "Federal Register /Vol. 82, No. 96 / Friday, May 19, 2017" (PDF).
  29. ^ Chen X, Chen Y, Liang R, Xiang L, Li J, Zhu Y, et al. (November 2021). "Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice". Molecular Cancer Therapeutics. 21 (1): 149–158. doi:10.1158/1535-7163.MCT-20-1025. PMC 8742776. PMID 34725191.
  30. ^ 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. S2CID 206693656.
  31. ^ 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): 6418–6428. doi:10.1158/1078-0432.CCR-14-1170. PMID 25320357. S2CID 24474000.
  32. ^ 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. 78 (13_Supplement). American Association for Cancer Research: 2549. doi:10.1158/1538-7445.AM2018-2549. S2CID 81043794.
  33. ^ a b Li D, Li N, Zhang YF, Fu H, Feng M, Schneider D, et al. (June 2020). "Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice". Gastroenterology. 158 (8): 2250–2265.e20. doi:10.1053/j.gastro.2020.02.011. PMC 7282931. PMID 32060001.
  34. ^ Kolluri A, Li D, Li N, Duan Z, Roberts LR, Ho M (2023-02-01). "Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC". Hepatology Communications. 7 (2): e0022. doi:10.1097/HC9.0000000000000022. ISSN 2471-254X. PMC 9851680. PMID 36691969.
  35. ^ NCT05003895

Further reading

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