Skip to main content

Advertisement

Log in

RETRACTED ARTICLE: Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

This article was retracted on 09 September 2023

This article has been updated

Abstract

Glypican-3 (GPC3) is a proteoglycan involved in migration, proliferation and cell survival modulation in several tissues. There are many reports demonstrating a downregulation of GPC3 expression in some human tumors, including mesothelioma, ovarian and breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their in vivo invasive and metastatic capacities together with a higher susceptibility to in vitro apoptosis. Currently, the signaling mechanism of GPC3 is not clear. First, it was speculated that GPC3 regulates the insulin-like growth factor (IGF) signaling system. This hypothesis, however, has been strongly challenged. 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Change history

References

  1. Filmus J, Selleck SB (2001) Glypicans: proteoglycans with a surprise. J Clin Invest 108:497–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nakato H, Futch TA, Selleck SB (1995) The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patternig during postembryonic development of the nervous system in Drosophila. Development 121:3687–3702

    Article  CAS  PubMed  Google Scholar 

  3. Baeg GH, Lin X, Khare N et al (2001) Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. Development 126:87–94

    Article  Google Scholar 

  4. Baeg GH, Perrimon N (2000) Functional binding of secreted molecules to heparan sulfate proteoglycans in Drosophila. Curr Opin Cell Biol 12(5):575–580

    Article  CAS  PubMed  Google Scholar 

  5. Desbordes SC, Sanson B (2003) The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila. Development 130(25):6245–6255

    Article  CAS  PubMed  Google Scholar 

  6. Habas R, Dawid IB, He X (2003) Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. Genes Dev 17(2):295–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuhl M, Geis K, Sheldahl LC et al (2001) Antagonistic regulation of convergent extension movements in Xenopus by Wnt/beta-catenin and Wnt/Ca2 + signaling. Mech Dev 106(1–2):61–76

    Article  CAS  PubMed  Google Scholar 

  8. Schambony A, Kunz M, Gradl D (2004) Cross-regulation of Wnt signaling and cell adhesion. Differentiation 72(7):307–318

    Article  CAS  PubMed  Google Scholar 

  9. Ilyas M (2005) Wnt signalling and the mechanistic basis of tumour development. J Pathol 205(2):130–144

    Article  CAS  PubMed  Google Scholar 

  10. Pilia G, Hughes-Benzie RM, MacKenzie A et al (1996) Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 12(3):241–247

    Article  CAS  PubMed  Google Scholar 

  11. Cano-Gauci DF, Song HH, Yang H et al (1999) Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. J Cell Biol 146(1):255–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dueñas-Gonzalez A, Kaya M, Shi W et al (1998) OCI 5/GPC3, a glypican encoded by a gene that is mutated in the Simpson-Golabi-Behmel overgrowth syndrome, induces apoptosis in a cell-specific manner. J Cell Biol 141:1407–1414

    Article  Google Scholar 

  13. Peters MG, Farias E, Colombo L et al (2003) Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. Breast Cancer Res Treat 80(2):221–232

    Article  CAS  PubMed  Google Scholar 

  14. Lin H, Huber R, Schlessinger D et al (1999) Frequent silencing of the GPC3 gene in ovarian cancer cell lines. Cancer Res 59(4):807–810

    CAS  PubMed  Google Scholar 

  15. Murthy SS, Shen T, De Rienzo A et al (2000) Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma. Oncogene 19(3):410–416

    Article  CAS  PubMed  Google Scholar 

  16. Xiang YY, Ladeda V, Filmus J (2001) Glypican-3 expression is silenced in human breast cancer. Oncogene 20(50):7408–7412

    Article  CAS  PubMed  Google Scholar 

  17. Weksberg R, Squire JA, Templeton DM (1996) Glypicans: a growing trend. Nat Genet 12(3):225–227

    Article  CAS  PubMed  Google Scholar 

  18. Song HH, Shi W, Filmus J (1997) OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. J Biol Chem 272:7574–7577

    Article  CAS  PubMed  Google Scholar 

  19. Chiao E, Fisher P, Crisponi L et al (2002) Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling. Dev Biol 243(1):185–206

    Article  CAS  PubMed  Google Scholar 

  20. Song HH, Shi W, Xiang YY et al (2005) The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280(3):2116–2125

    Article  CAS  PubMed  Google Scholar 

  21. Capurro MI, Shi W, Sandal S et al (2005) Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth. J Biol Chem 280(50):41201–41206

    Article  CAS  PubMed  Google Scholar 

  22. Capurro MI, Xiang YY, Lobe C et al (2005) Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res 65(14):6245–6254

    Article  CAS  PubMed  Google Scholar 

  23. De Cat B, Muyldermans SY, Coomans C et al (2003) Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol 163(3):625–635

    Article  PubMed  PubMed Central  Google Scholar 

  24. Song HH, Shi W, Xiang YY et al (2005) The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 280(3):2116–2125

    Article  CAS  PubMed  Google Scholar 

  25. Urtreger A, Ladeda V, Puricelli L et al (1997) Modulation of fibronectin expression and proteolytic activity associated with the invasive and metastatic phenotype in two murine mammary cell lines. Int J Oncol 11:489–496

    CAS  PubMed  Google Scholar 

  26. Bal de Kier Joffé E, Puricelli L, Vidal MC et al (1983) Characterization of two murine mammary adenocarcinoma tumors with different metastatic ability. J Exp Clin Cancer Res 2:151–160

    Google Scholar 

  27. Mizushima S, Nagata S (1990) pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res 18(17):5322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Filmus J, Shi W, Wong ZM et al (1995) Identification of a new membrane-bound heparan sulphate proteoglycan. Biochem J 311(Pt 2):561–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  30. Soriano S, Kang DE, Fu M et al (2001) Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J Cell Biol 152(4):785–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Coso OA, Chiariello M, Yu JC et al (1995) The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81(7):1137–1146

    Article  CAS  PubMed  Google Scholar 

  32. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hwang SG, Yu SS, Lee SW et al (2005) Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway. FEBS Lett 579(21):4837–4842

    Article  CAS  PubMed  Google Scholar 

  34. Wagner EF (2002) Functions of AP1 (Fos/Jun) in bone development. Ann Rheum Dis 61(Suppl 2):ii40–ii42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Veeman MT, Axelrod JD, Moon RT (2003) A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell 5(3):367–377

    Article  CAS  PubMed  Google Scholar 

  36. Willipinski-Stapelfeldt B, Riethdorf S, Assmann V et al (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11(22):8006–8014

    Article  CAS  PubMed  Google Scholar 

  37. Nobes CD, Hall A (1995) Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility. Biochem Soc Trans 23(3):456–459

    Article  CAS  PubMed  Google Scholar 

  38. Kuhl M, Sheldahl LC, Malbon CC et al (2000) Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem 275(17):12701–12711

    Article  CAS  PubMed  Google Scholar 

  39. Boutros M, Paricio N, Strutt DI et al (1998) Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94(1):109–118

    Article  CAS  PubMed  Google Scholar 

  40. Pandur P, Maurus D, Kuhl M (2002) Increasingly complex: new players enter the Wnt signaling network. Bioessays 24(10):881–884

    Article  CAS  PubMed  Google Scholar 

  41. Weeraratna AT, Jiang Y, Hostetter G et al (2002) Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1(3):279–288

    Article  CAS  PubMed  Google Scholar 

  42. Tada M, Concha ML, Heisenberg CP (2002) Non-canonical Wnt signalling and regulation of gastrulation movements. Semin Cell Dev Biol 13(3):251–260

    Article  CAS  PubMed  Google Scholar 

  43. Ohkawara B, Yamamoto TS, Tada M et al (2003) Role of glypican 4 in the regulation of convergent extension movements during gastrulation in Xenopus laevis. Development 130(10):2129–2138

    Article  CAS  PubMed  Google Scholar 

  44. Pecina-Slaus N (2003) Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int 3(1):17

    Article  PubMed  PubMed Central  Google Scholar 

  45. Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115(Pt 21):3977–3978

    Article  CAS  PubMed  Google Scholar 

  46. Nelson WJ, Nusse R (2004) Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303(5663):1483–1487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Christofori G (2003) Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. Embo J 22(10):2318–2323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gupta S, Barrett T, Whitmarsh AJ et al (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. Embo J 15(11):2760–2770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Minden A, Lin A, Claret FX et al (1995) Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81(7):1147–1157

    Article  CAS  PubMed  Google Scholar 

  50. Coffey ET, Hongisto V, Dickens M et al (2000) Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. J Neurosci 20(20):7602–7613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J Cell Sci 117(Pt 20):4619–4628

    Article  CAS  PubMed  Google Scholar 

  52. Zhang L, Wang W, Hayashi Y et al (2003) A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure. Embo J 22(17):4443–4454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Barr RK, Bogoyevitch MA (2001) The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). Int J Biochem Cell Biol 33(11):1047–1063

    Article  CAS  PubMed  Google Scholar 

  54. Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development. Curr Opin Cell Biol 10(2):205–219

    Article  CAS  PubMed  Google Scholar 

  55. Xia Y, Karin M (2004) The control of cell motility and epithelial morphogenesis by Jun kinases. Trends Cell Biol 14(2):94–101

    Article  CAS  PubMed  Google Scholar 

  56. Neilson EG (2006) Mechanisms of disease: Fibroblasts-a new look at an old problem. Nat Clin Pract Nephrol 2(2):101–108

    Article  CAS  PubMed  Google Scholar 

  57. Brabletz T, Hlubek F, Spaderna S et al (2005) Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 179(1–2):56–65

    Article  CAS  PubMed  Google Scholar 

  58. Bafico A, Liu G, Goldin L et al (2004) An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 6(5):497–506

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work was supported by grants from FONCyT (PICT 14088, Préstamo BID 1728/OC-AR) and from the University of Buenos Aires (UBACyT M068). We would like to give our thanks to Guillermo Peluffo for technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to María Giselle Peters.

Additional information

Lydia Puricelli, Elisa Bal de Kier Joffé and María Giselle Peters are the members of the National Council of Scientific and Technical Research (CONICET).

About this article

Cite this article

Stigliano, I., Puricelli, L., Filmus, J. et al. RETRACTED ARTICLE: Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation. Breast Cancer Res Treat 114, 251–262 (2009). https://doi.org/10.1007/s10549-008-0009-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-0009-2

Keywords

Navigation