GPC3
Identifiers
AliasesGPC3, DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, SGBS1, Glypican 3
External IDsOMIM: 300037 MGI: 104903 HomoloGene: 20944 GeneCards: GPC3
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 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 might interact with FAT1 on the cell surface.[15]

Disease linkage

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

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[18] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[19] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[20] The YP7 murine antibody has been humanized and named as 'hYP7'.[21] 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

To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33,[22] YP7,[20] HN3[12] and HS20[13][23] have been made and widely tested. 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.[20] These antibodies have been humanized (e.g. hYP7) via antibody engineering for clinical applications.[21] 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 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.[33] CAR (hYP7) T cells are being evaluated at a clinical trial (NCT05003895) at the NIH.

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000147257 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 1 2 "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. 1 2 3 4 5 6 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. 1 2 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. 1 2 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. 1 2 3 4 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 3 4 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. ↑ 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.
  19. ↑ 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.
  20. 1 2 3 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.
  21. 1 2 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. American Association for Cancer Research. 78 (13_Supplement): 2549. doi:10.1158/1538-7445.AM2018-2549. S2CID 81043794.
  33. 1 2 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.

Further reading

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