Glypican 3

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An Error has occurred retrieving Wikidata item for infobox 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

File:Schematic of the glypican-3 protein..tif
Schematic of the glypican-3 (GPC3) protein[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 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 has been found to regulate Wnt/β-catenin and Yap signaling pathways.[5][6][7][8][9][10][11][12] GPC3 interacts with both Wnt and frizzled (FZD) to form a complex and triggers downstream signaling.[7][13] 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.[13] Blocking the Wnt binding domain on GPC3 using the HN3 single domain antibody can inhibit Wnt activation.[13] 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.[6] GPC3 also modulates Yap signaling.[8] It interacts with FAT1, a potential upstream cell surface receptor of YAP1 in human cells.[11] GPC3 is also found to bind Alpha-fetoprotein in liver cancer.[14]

Disease linkage

Deletion mutations in this gene are associated with Simpson–Golabi–Behmel syndrome.[1]

Diagnostic utility

Glypican 3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC)[15] and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.[16] Using the YP7 murine monoclonal antibody, GPC3 protein expression is found in HCC, not in normal liver and cholangiocarcinoma.[17] The YP7 murine antibody has been humanized and named as 'hYP7'.[18] 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.[5]

Therapeutic potential

To validate GPC3 as a therapeutic target in liver cancer, the anti-GPC3 therapeutic antibodies GC33,[19] YP7,[17] HN3[8] and HS20[9][20] 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.[17] The antibody has been humanized (named hYP7) via antibody engineering for clinical applications.[18] The Ho lab has also identified the human single-domain antibody ('human nanobody') HN3[8] targeting the N-lobe of GPC3 [13] and the human monoclonal antibody HS20[9][20] 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,[10][21][22] the antibody-drug conjugates based on hYP7[23] and the T-cell engaging bispecific antibodies derived from YP7[24][25] and GC33,[26] have been developed for treating liver cancer. The chimeric antigen receptor (CAR) T cell immunotherapies based on GC33,[27] hYP7[28][29] and HN3[30] 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.[29] CAR (hYP7) T cells are being evaluated at a clinical trial at the NIH.[31]

See also

References

  1. ↑ 1.0 1.1 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.
  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): 184–189. doi:10.1016/j.yexmp.2006.10.010. PMID 17258707.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 8.2 8.3 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.
  9. ↑ 9.0 9.1 9.2 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.
  10. ↑ 10.0 10.1 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.
  11. ↑ 11.0 11.1 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.
  12. ↑ 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.
  13. ↑ 13.0 13.1 13.2 13.3 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 17.0 17.1 17.2 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.
  18. ↑ 18.0 18.1 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.
  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): 9832–9838. doi:10.1158/0008-5472.CAN-08-1973. PMID 19047163.
  20. ↑ 20.0 20.1 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ "Federal Register /Vol. 82, No. 96 / Friday, May 19, 2017" (PDF).
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 29.0 29.1 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.
  30. ↑ 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.
  31. ↑ NCT05003895

Further reading

External links

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