Skip to main content

Advertisement

SpringerLink
Log in

HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells

  • Original paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

We have previously shown that transduction of HOXD3, one of homeobox genes, into human lung cancer A549 cells enhances cell motility, invasion and metastasis. In the present study, we examined the roles of integrin β3 which was up-regulated by HOXD3-overexpression in the HOXD3-induced motility of A549 cells. We first established integrin β3-transfectants and compared their motile activity to those of the HOXD3-transfected, control-transfected and parental cells by three different assays. The integrin β3-transfectants as well as the HOXD3-transfectants formed heterodimer with integrin αv subunit, and showed highly motile activities assessed by haptotaxis or phagokinetic track assay compared to the control transfectants or parental cells. In vitro wound-healing assay revealed that migratory activities were graded as the HOXD3-transfectants > the integrin β3-transfectants > the control transfectants or parental cells. E-cadherin was expressed in the integrin β3-transfectants but not expressed in the HOXD3-transfectants. An addition of function-blocking antibody to E-cadherin into the wound-healing assay promoted the migratory activity of the integrin β3-transfectants, suggesting that E-cadherin prevented the cells from dissociating from the wound edges. These results indicate that increased expression of integrin αv β3 and loss of E-cadherin by HOXD3-overexpression are responsible for the enhanced motility and dissociation.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Poste G, Fidler IJ (1980) The pathogenesis of cancer metastasis. Nature 283:139–146

    Article  PubMed  CAS  Google Scholar 

  2. Nicolson GL (1988) Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 948:175–224

    PubMed  CAS  Google Scholar 

  3. Gehring WJ, Hiromi Y (1986) Homeotic genes and the homeobox. Annu Rev Genet 20:147–173

    Article  PubMed  CAS  Google Scholar 

  4. Graham A, Papalopulu N, Krumlauf R (1989) The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 57:367–378

    Article  PubMed  CAS  Google Scholar 

  5. McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68:283–302

    Article  PubMed  CAS  Google Scholar 

  6. Levine M, Hoey T (1988) Homeobox proteins as sequence-specific transcription factors. Cell 55:537–540

    Article  PubMed  CAS  Google Scholar 

  7. Ruddle FH, Bartels JL, Bentley KL et al (1994) Evolution of Hox genes. Annu Rev Genet 28:423–442

    Article  PubMed  CAS  Google Scholar 

  8. Takahashi Y, Hamada J, Murakawa K et al (2004) Expression profiles of 39 HOX genes in normal human adult organs and anaplastic thyroid cancer cell lines by quantitative real-time RT-PCR system. Exp Cell Res 293:144–153

    Article  PubMed  CAS  Google Scholar 

  9. Cillo C, Cantile M, Faiella A et al (2001) Homeobox genes in normal and malignant cells. J Cell Physiol 188:161–169

    Article  PubMed  CAS  Google Scholar 

  10. Jones FS, Prediger EA, Bittner DA et al (1992) Cell adhesion molecules as targets for Hox genes: neural cell adhesion molecule promoter activity is modulated by cotransfection with Hox-2.5 and -2.4. Proc Natl Acad Sci USA 89:2086–2090

    Article  PubMed  CAS  Google Scholar 

  11. Jones FS, Holst BD, Minowa O et al (1993) Binding and transcriptional activation of the promoter for the neural cell adhesion molecule by HoxC6 (Hox-3.3). Proc Natl Acad Sci USA 90:6557–6561

    Article  PubMed  CAS  Google Scholar 

  12. Cillo C, Cantile M, Mortarini R et al (1996) Differential patterns of HOX gene expression are associated with specific integrin and ICAM profiles in clonal populations isolated from a single human melanoma metastasis. Int J Cancer 66:692–697

    Article  PubMed  CAS  Google Scholar 

  13. Naora H, Montz FJ, Chai CY et al (2001) Aberrant expression of homeobox gene HOXA7 is associated with mullerian-like differentiation of epithelial ovarian tumors and the generation of a specific autologous antibody response. Proc Natl Acad Sci USA 98:15209–15214

    Article  PubMed  CAS  Google Scholar 

  14. Taniguchi Y, Komatsu N, Moriuchi T (1995) Overexpression of the HOX4A (HOXD3) homeobox gene in human erythroleukemia HEL cells results in altered adhesive properties. Blood 85:2786–2794

    PubMed  CAS  Google Scholar 

  15. Boudreau N, Andrews C, Srebrow A et al (1997) Induction of the angiogenic phenotype by Hox D3. J Cell Biol 139:257–264

    Article  PubMed  CAS  Google Scholar 

  16. Hamada J, Omatsu T, Okada F et al (2001) Overexpression of homeobox gene HOXD3 induces coordinate expression of metastasis-related genes in human lung cancer cells. Int J Cancer 93:516–525

    Article  CAS  Google Scholar 

  17. Cheresh DA, Spiro RC (1987) Biosynthetic and functional properties of an Arg-Gly-Asp-directed receptor involved in human melanoma cell attachment to vitronectin, fibrinogen, and von Willebrand factor. J Biol Chem 262:17703–17711

    PubMed  CAS  Google Scholar 

  18. Filardo EJ, Brooks PC, Deming SL et al (1995) Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. J Cell Biol 130:441–450

    Article  PubMed  CAS  Google Scholar 

  19. Boyer B, Tucker GC, Valles AM et al (1989) Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. J Cell Biol 109:1495–1509

    Article  PubMed  CAS  Google Scholar 

  20. Behrens J, Mareel MM, Van Roy FM et al (1989) Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol 108:2435–2447

    Article  PubMed  CAS  Google Scholar 

  21. Vleminckx K, Vakaet L Jr, Mareel M et al (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66:107–119

    Article  PubMed  CAS  Google Scholar 

  22. Mareel MM, Behrens J, Birchmeier W et al (1991) Down-regulation of E-cadherin expression in Madin Darby canine kidney (MDCK) cells inside tumors of nude mice. Int J Cancer 47:922–928

    PubMed  CAS  Google Scholar 

  23. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25

    Article  PubMed  CAS  Google Scholar 

  24. Albrecht-Buehler G (1977) The phagokinetic tracks of 3T3 cells. Cell 11:395–404

    Article  PubMed  CAS  Google Scholar 

  25. Albrecht-Buehler G (1997) Phagokinetic tracks of 3T3 cells: parallels between the orientation of track segments and of cellular structures which contain actin or tubulin. Cell 12:333–339

    Article  Google Scholar 

  26. Shattil SJ (1995) Function and regulation of the beta 3 integrins in hemostasis and vascular biology. Thromb Haemost 74:149–155

    PubMed  CAS  Google Scholar 

  27. Imamura F, Horai T, Mukai M et al (1993) Induction of in vitro tumor cell invasion of cellular monolayers by lysophosphatidic acid or phospholipase D. Biochem Biophys Res Commun 193:497–503

    Article  PubMed  CAS  Google Scholar 

  28. Schneller M, Vuori K, Ruoslahti E (1997) Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. EMBO J 16:5600–5607

    Article  PubMed  CAS  Google Scholar 

  29. Borges E, Jan Y, Ruoslahti E (2000) Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. J Biol Chem 275:39867–39873

    Article  PubMed  CAS  Google Scholar 

  30. Baron W, Shattil SJ, ffrench-Constant C (2002) The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of alpha(v)beta3 integrins. EMBO J 21:1957–1966

    Article  PubMed  CAS  Google Scholar 

  31. Hirohashi S (1998) Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153:333–339

    PubMed  CAS  Google Scholar 

  32. Miyazaki YJ, Hamada J, Tada M et al (2002) HOXD3 enhances motility and invasiveness through the TGF-beta-dependent and -independent pathways in A549 cells. Oncogene 21:798–808

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Ms. Masako Yanome for her help in preparing the manuscript. This work was supported by a Grant-in-Aid for Scientific Research (B) and a Grant-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan

    Hironori Ohta, Jun-ichi Hamada, Mitsuhiro Tada, Tetsuya Aoyama, Keiji Furuuchi, Yoko Takahashi & Tetsuya Moriuchi

  2. Oral and Maxillofacial Surgery, Department of Oral Patho-biological Medicine, Graduate School of Dental Medicine, Hokkaido University, Kita-13, Nishi-7, Kita-ku, Sapporo, 060-8586, Japan

    Hironori Ohta & Yasunori Totsuka

Authors
  1. Hironori Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-ichi Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuhiro Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuya Aoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiji Furuuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoko Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasunori Totsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tetsuya Moriuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun-ichi Hamada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohta, H., Hamada, Ji., Tada, M. et al. HOXD3-overexpression increases integrin αvβ3 expression and deprives E-cadherin while it enhances cell motility in A549 cells. Clin Exp Metastasis 23, 381–390 (2006). https://doi.org/10.1007/s10585-006-9047-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-006-9047-5

Keywords

Search

Navigation