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Gene Review

GPC3  -  glypican 3

Homo sapiens

Synonyms: DGSX, GTR2-2, Glypican-3, Intestinal protein OCI-5, MXR7, ...
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Disease relevance of GPC3

  • In addition, only 1 of 20 patients with hepatitis plus liver cirrhosis displayed elevated levels of serum GPC3 [1].
  • RESULTS: Immunohistochemical studies showed that GPC3 is expressed in 72% of HCCs (21 of 29), whereas it is not detectable in hepatocytes from normal liver and benign liver diseases [1].
  • In our laboratory, we have recently demonstrated that GPC3 promotes the growth of hepatocellular carcinomas (HCCs) by stimulating canonical Wnt signaling [2].
  • CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage [3].
  • GPC3 was not expressed in normal kidney tissues obtained from the corresponding Wilms' tumor patients, suggesting that in these cancer cells expression was not repressed (or was activated) [4].
  • GPC3 is involved in the regulation of cell proliferation and survival in specific cell types. LM3, a murine mammary tumor cell line unable to express GPC3, was stably transfected with the rat GPC3 gene to analyze its role in tumor progression. Upon injection into syngeneic BALB/c mice GPC3-LM3 clones showed less local invasiveness and developed fewer spontaneous and experimental lung metastasis than controls. GPC3-expressing cells were more sensitive to apoptosis induced by serum depletion, exhibited a delay in the first steps of spreading and were less motile than controls. On the other hand, LM3-GPC3 cells were significantly more adherent to FN than control ones. We observed that GPC3 transfectants presented a higher expression of E-Cadherin and b -Catenin, molecules which down regulation has been associated with tumor progression. Exogenous TGF- b increased MMP-9 activity in both control and GPC3-expressing cells, but did not modulate MMP-2. Contrarily, GPC3 expression prevented the increase of MMP-2 activity induced by IGF-II. Our results suggest that GPC3 has a remarkable protective role against mammary cancer progression [5].
  • Tumorigenesis is associated with changes in the proteoglycans (PGs) synthesis. Our group is focused on the analysis of the role of GPC3 on tumor progression of the mammary gland. We have previously investigated the effect of GPC3 reexpression on the invasive and metastatic behavior of the GPC3 -negative LM3 murine mammary adenocarcinoma cell line. Although GPC3 reexpression did not change tumor growth rate at the s.c. site, it reduced the ability of LM3 cells to invade the dermis and to form lung metastasis after s.c. or i.v. inoculation. This led us to propose that GPC3 would be acting as a metastasis suppressor in breast cancer [6].

Psychiatry related information on GPC3


High impact information on GPC3

  • Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome [8].
  • The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS [8].
  • The values and limitations of glypican-3 as a novel tumor marker for hepatocellular carcinoma from clinical and economic viewpoints [9].
  • Interestingly, in most cases, there was no correlation between GPC3 and AFP values [1].
  • Our data imply that the Simpson-Golabi-Behmel syndrome may in part result from a loss of GPC3 controls on Wnt signaling, and suggest that this function requires the cooperation of both the protein and the heparan sulfate moieties of the proteoglycan [10].

Chemical compound and disease context of GPC3


Biological context of GPC3

  • Six SGBS patients showed point mutations in GPC3 [13].
  • Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene [13].
  • A GPC3 protein that reproduces this mutation is poorly processed and fails to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation [13].
  • Because there is increasing evidence indicating that the structural requirements for GPC3 activity are cell type specific, we decided to investigate whether GPC3 needs to be processed by convertases to stimulate cell proliferation and Wnt signaling in HCC cells [2].
  • To investigate the role of overexpressed GPC3 in liver cancer, we analyzed its effects on cell growth of hepatoblastoma-derived cells [14].

Anatomical context of GPC3

  • By Western blot analysis carried out with a monoclonal anti-GPC3 antibody we generated, the GPC3 protein was found to be overexpressed in 6 hepatoma cell lines, HepG2, Hep3B, HT17, HuH6, HuH7 and PLC/PRF/5, as well as 22 tumors (42.3%) [14].
  • A full-length promoter construct was also highly active in HeLa cells, which do not express endogenous GPC3 [15].
  • GPC3 mRNA expression increased markedly during trophoblast differentiation [16].
  • GPC3 expression was observed in neoplastic cells of yolk-sac tumor (YST) (25/25), teratoma (2/10), components of syncytiotrophoblastic giant cells (STGCs) (10/14), and choriocarcinoma (1/3), but none in intratubular germ-cell neoplasias, unclassified type (0/33), seminomas (0/61), or embryonal carcinoma (0/19) [17].
  • By contrast, fibroblast cell lines derived from normal placentae did not express GPC3 in culture [16].
  • Glypicans represent a family of cell surface proteoglycans. Loss-of-function mutations in the human glypican-3 (GPC3) gene results in the Simpson-Golabi- Behmel syndrome, characterized by severe malformations and pre- and postnatal overgrowth. Because the expression of GPC3 during human embryonic and fetal periods remains largely unknown, we investigated by immunohistochemistry its pattern of expression during four periods of human development covering the embryonic period (P1) from 5 to 8 weeks of development, and the fetal periods (P2, P3 and P4) from 9 to 28 weeks of development. [18]

Associations of GPC3 with chemical compounds


Physical interactions of GPC3

  • On the other hand, we have found that OCI-5 interacts with FGF-2, as has already been shown for glypican-1 [20].
  • As part of characterizing AF IGF-II binding, we also show that the prominent high-molecular mass IGF-II-binding protein in preterm AF is GPC3, a protein of the glypican family, recently cloned because its mutations predispose to Wilms' tumor [24].

Regulatory relationships of GPC3

  • Our data suggest that GPC3 plays a growth-suppressing role in hepatoma and provide cell biological evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by downregulating IGF2 [12].
  • Here we show that based on oligonucleotide array analysis, GPC3 was upregulated in hepatocellular carcinoma (HCC) [14].
  • Gpc3 expression persists in atypical duct-like structures and liver lesions of animals subjected to the Solt-Farber model of initiation and promotion of liver cancer expressing CK-19 [25].
  • Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one . We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival. [26]
  • Currently, the signaling mechanism of GPC3 is not clear. Recently, several reports indicated that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling. Here we provide new data demonstrating that GPC3 regulates Wnt pathway in the metastatic adenocarcinoma mammary LM3 cell line. We found that GPC3 is able to inhibit canonical Wnt signals involved in cell proliferation and survival, as well as it is able to activate non canonical pathway, which directs cell morphology and migration. This is the first report indicating that breast tumor cell malignant properties can be reverted, at least in part, by GPC3 modulation of Wnt signaling. Our results are consistent with the potential role of GPC3 as a metastasis suppressor. [27]

Other interactions of GPC3

  • Unlike the glypican-3 message, the glypican-4 message is nearly ubiquitous [28].
  • Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates [29].
  • No correlation was found between expression of GPC3 and the known indicator of neuroblastoma prognosis MYCN mRNA [4].
  • We also found that FGF2-mediated cell proliferation was inhibited by GPC3 [30].
  • We report here that we have transfected OCI-5 into two different cell lines, and we have not been able to detect an interaction between the OCI-5 proteoglycan produced by the transfected cells and IGF-2 [20].

Analytical, diagnostic and therapeutic context of GPC3



  1. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Capurro, M., Wanless, I.R., Sherman, M., Deboer, G., Shi, W., Miyoshi, E., Filmus, J. Gastroenterology (2003) [Pubmed]
  2. Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth. Capurro, M.I., Shi, W., Sandal, S., Filmus, J. J. Biol. Chem. (2005) [Pubmed]
  3. Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels. Ikuta, Y., Nakatsura, T., Kageshita, T., Fukushima, S., Ito, S., Wakamatsu, K., Baba, H., Nishimura, Y. Clin. Cancer Res. (2005) [Pubmed]
  4. Expression of glypican 3 (GPC3) in embryonal tumors. Saikali, Z., Sinnett, D. Int. J. Cancer (2000) [Pubmed]
  5. Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. Peters, M.G., Farías, E., Colombo, L., Filmus, J., Puricelli, L., Bal de Kier Joffé, E. Breast. Cancer. Res. Treat. (2003) [Pubmed]
  6. Metastasis suppressors: basic and translational advances. Buchanan, C., Lago Huvelle, M.A., Peters, M.G. Curr. Pharm. Biotechnol. (2011) [Pubmed]
  7. Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature. Mahady, G.B. The Journal of cardiovascular nursing. (2002) [Pubmed]
  8. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Pilia, G., Hughes-Benzie, R.M., MacKenzie, A., Baybayan, P., Chen, E.Y., Huber, R., Neri, G., Cao, A., Forabosco, A., Schlessinger, D. Nat. Genet. (1996) [Pubmed]
  9. The values and limitations of glypican-3 as a novel tumor marker for hepatocellular carcinoma from clinical and economic viewpoints. Moriguchi, H., Sato, C. Gastroenterology (2004) [Pubmed]
  10. Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. De Cat, B., Muyldermans, S.Y., Coomans, C., Degeest, G., Vanderschueren, B., Creemers, J., Biemar, F., Peers, B., David, G. J. Cell Biol. (2003) [Pubmed]
  11. The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor. Kim, H., Xu, G.L., Borczuk, A.C., Busch, S., Filmus, J., Capurro, M., Brody, J.S., Lange, J., D'Armiento, J.M., Rothman, P.B., Powell, C.A. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  12. Growth promotion of HepG2 hepatoma cells by antisense-mediated knockdown of glypican-3 is independent of insulin-like growth factor 2 signaling. Sung, Y.K., Hwang, S.Y., Farooq, M., Kim, J.C., Kim, M.K. Exp. Mol. Med. (2003) [Pubmed]
  13. Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Veugelers, M., Cat, B.D., Muyldermans, S.Y., Reekmans, G., Delande, N., Frints, S., Legius, E., Fryns, J.P., Schrander-Stumpel, C., Weidle, B., Magdalena, N., David, G. Hum. Mol. Genet. (2000) [Pubmed]
  14. Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. Midorikawa, Y., Ishikawa, S., Iwanari, H., Imamura, T., Sakamoto, H., Miyazono, K., Kodama, T., Makuuchi, M., Aburatani, H. Int. J. Cancer (2003) [Pubmed]
  15. Multiple Sp1 sites efficiently drive transcription of the TATA-less promoter of the human glypican 3 (GPC3) gene. Huber, R., Schlessinger, D., Pilia, G. Gene (1998) [Pubmed]
  16. Glypican-3 (GPC3) expression in human placenta: localization to the differentiated syncytiotrophoblast. Khan, S., Blackburn, M., Mao, D.L., Huber, R., Schlessinger, D., Fant, M. Histol. Histopathol. (2001) [Pubmed]
  17. Oncofetal protein glypican-3 in testicular germ-cell tumor. Ota, S., Hishinuma, M., Yamauchi, N., Goto, A., Morikawa, T., Fujimura, T., Kitamura, T., Kodama, T., Aburatani, H., Fukayama, M. Virchows Arch. (2006) [Pubmed]
  18. Expression pattern of glypican-3 (GPC3) during human embryonic and fetal development. Iglesias, B.V., Centeno, G., Pascuccelli, H., Ward, F., Peters, M.G., Filmus, J., Puricelli, L., de Kier Joffé, E.B. Histol. Histopathol. (2008) [Pubmed]
  19. The roles of supernumerical X chromosomes and XIST expression in testicular germ cell tumors. Kawakami, T., Okamoto, K., Sugihara, H., Hattori, T., Reeve, A.E., Ogawa, O., Okada, Y. J. Urol. (2003) [Pubmed]
  20. OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. Song, H.H., Shi, W., Filmus, J. J. Biol. Chem. (1997) [Pubmed]
  21. Frequent silencing of the GPC3 gene in ovarian cancer cell lines. Lin, H., Huber, R., Schlessinger, D., Morin, P.J. Cancer Res. (1999) [Pubmed]
  22. Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells. Wichert, A., Stege, A., Midorikawa, Y., Holm, P.S., Lage, H. Oncogene (2004) [Pubmed]
  23. Glypican-3 is overexpressed in human hepatocellular carcinoma. Sung, Y.K., Hwang, S.Y., Park, M.K., Farooq, M., Han, I.S., Bae, H.I., Kim, J.C., Kim, M. Cancer Sci. (2003) [Pubmed]
  24. Developmental regulation of the soluble form of insulin-like growth factor-II/mannose 6-phosphate receptor in human serum and amniotic fluid. Xu, Y., Papageorgiou, A., Polychronakos, C. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  25. The oncofetal protein glypican-3 is a novel marker of hepatic progenitor/oval cells. Grozdanov, P.N., Yovchev, M.I., Dabeva, M.D. Lab. Invest. (2006) [Pubmed]
  26. Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways. Buchanan, C., Stigliano, I., Garay-Malpartida, H.M., Rodrigues Gomes, L., Puricelli, L., Sogayar, M.C., Bal de Kier Joffé, E., Peters, M.G. Breast. Cancer. Res. Treat. (2010) [Pubmed]
  27. Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation. Stigliano, I., Puricelli, L., Filmus, J., Sogayar, M.C., Bal de Kier Joffé, E., Peters, M.G. Breast. Cancer. Res. Treat. (2009) [Pubmed]
  28. 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. Veugelers, M., Vermeesch, J., Watanabe, K., Yamaguchi, Y., Marynen, P., David, G. Genomics (1998) [Pubmed]
  29. Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. Cano-Gauci, D.F., Song, H.H., Yang, H., McKerlie, C., Choo, B., Shi, W., Pullano, R., Piscione, T.D., Grisaru, S., Soon, S., Sedlackova, L., Tanswell, A.K., Mak, T.W., Yeger, H., Lockwood, G.A., Rosenblum, N.D., Filmus, J. J. Cell Biol. (1999) [Pubmed]
  30. Cellular changes resulting from forced expression of glypican-3 in hepatocellular carcinoma cells. Kwack, M.H., Choi, B.Y., Sung, Y.K. Mol. Cells (2006) [Pubmed]
  31. Usefulness of the novel oncofetal antigen glypican-3 for diagnosis of hepatocellular carcinoma and melanoma. Nakatsura, T., Nishimura, Y. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. (2005) [Pubmed]
  32. Identification of glypican-3 as a novel tumor marker for melanoma. Nakatsura, T., Kageshita, T., Ito, S., Wakamatsu, K., Monji, M., Ikuta, Y., Senju, S., Ono, T., Nishimura, Y. Clin. Cancer Res. (2004) [Pubmed]
  33. Analysis of exon/intron structure and 400 kb of genomic sequence surrounding the 5'-promoter and 3'-terminal ends of the human glypican 3 (GPC3) gene. Huber, R., Crisponi, L., Mazzarella, R., Chen, C.N., Su, Y., Shizuya, H., Chen, E.Y., Cao, A., Pilia, G. Genomics (1997) [Pubmed]
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