Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Bone morphogenetic protein 3B silencing in non-small-cell lung cancer

Oncogene volume 23, pages 3521–3529 (2004)Cite this article

Abstract

Bone morphogenetic protein 3B (BMP3B) is a member of the TGF-β superfamily. The BMP3B promoter sequence was previously identified as a target for aberrant DNA methylation in non-small-cell lung cancer (NSCLC). Aberrant DNA hypermethylation in the BMP3B promoter is associated with downregulation of BMP3B transcription in both primary human lung cancers as well as lung cancer cell lines. In order to understand the mechanisms of BMP3B silencing in lung cancer, a sample set of 91 primary NSCLCs was used to detect aberrant BMP3B promoter methylation, mutations in the coding sequence of BMP3B, and loss of heterozygosity (LOH). Our results showed that 45 of 91 (or 49.5%) tested primary NSCLCs exhibited increased promoter methylation, and 40% demonstrated LOH in at least one of the flanking microsatellite markers sJRH and D10S196 (63 kb upstream or 3.338 Mbp downstream of BMP3B). The lung cancer cell line A549, a type II alveolar epithelial human lung cancer cell line, is characterized by aberrant DNA promoter methylation. We used retroviral vector constructs containing the BMP3B cDNA to re-express the gene in A549 cells and to investigate the effects on cell growth. No change in the cell growth rate was observed after BMP3B re-expression, as compared to the vector controls. Although the number of colonies formed in anchorage-dependent assays was only slightly decreased, the colony-forming ability of A549 cells after BMP3B expression in anchorage-independent assays in soft agar was significantly reduced to 10% (P<0.005, t-test). Moreover, the in vivo tumorigenicity assay in nude mice indicated that cells re-expressing BMP3B grew significantly slower than cells not expressing BMP3B (P<0.05, t-test). In conclusion, this study provides evidence that BMP3B expression is repressed by different mechanisms in lung cancer, and that the silencing of BMP3B promotes lung tumor development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Akhurst RJ . (2002). J. Clin. Invest., 109, 1533–1536.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP . (1998). Adv. Cancer Res., 72, 141–196.

  • Caulin C, Scholl FG, Frontelo P, Gamallo C and Quintanilla M . (1995). Cell Growth Differ., 6, 1027–1035.

  • Colasante A, Mascetra N, Brunetti M, Lattanzio G, Diodoro M, Caltagirone S, Musiani P and Aiello FB . (1997). Am. J. Respir. Crit. Care Med., 156, 968–973.

  • Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, MS OD, Held WA, Cavenee WK and Plass C . (2000). Nat. Genet., 24, 132–138.

  • Dai Z, Lakshmanan RR, Zhu WG, Smiraglia DJ, Rush LJ, Fruhwald MC, Brena RM, Li B, Wright FA, Ross P, Otterson GA and Plass C . (2001). Neoplasia, 3, 314–323.

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.

  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y and Wang XF . (1995). Proc. Natl. Acad. Sci. USA, 92, 5545–5549.

  • Derynck R, Akhurst RJ and Balmain A . (2001). Nat. Genet., 29, 117–129.

  • Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS and Berger WH . (1987). Cancer Res., 47, 707–712.

  • Faucheux C, Ulysse F, Bareille R, Reddi AH and Amedee J . (1997). Biochem. Biophys. Res. Commun., 241, 787–793.

  • Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF and Minna JD . (2000). Cancer Res., 60, 4894–4906.

  • Hannon GJ and Beach D . (1994). Nature, 371, 257–261.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Hino J, Takao M, Takeshita N, Konno Y, Nishizawa T, Matsuo H and Kangawa K . (1996). Biochem. Biophys. Res. Commun., 223, 304–310.

  • Hubank M and Schatz DG . (1994). Nucleic Acids Res., 22, 5640–5648.

  • Keski-Oja J, Raghow R, Sawdey M, Loskutoff DJ, Postlethwaite AE, Kang AH and Moses HL . (1988). J. Biol. Chem., 263, 3111–3115.

  • Kiemer AK, Takeuchi K and Quinlan MP . (2001). Oncogene, 20, 6679–6688.

  • Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB and Nelson WG . (1994). Proc. Natl. Acad. Sci. USA, 91, 11733–11737.

  • Liang G, Gonzalgo ML, Salem C and Jones PA . (2002). Methods, 27, 150–155.

  • Massague J, Blain SW and Lo RS . (2000). Cell, 103, 295–309.

  • Miyazono K, Kusanagi K and Inoue H . (2001). J. Cell Physiol., 187, 265–276.

  • Oft M, Peli J, Rudaz C, Schwarz H, Beug H and Reichmann E . (1996). Genes Dev., 10, 2462–2477.

  • Plass C and Soloway PD . (2002). Eur. J. Hum. Genet., 10, 6–16.

  • Ridley A . (2000). Nature, 406, 466–467.

  • Samuel W, Nagineni CN, Kutty RK, Parks WT, Gordon JS, Prouty SM, Hooks JJ and Wiggert B . (2002). J. Biol. Chem., 277, 59–66.

  • Sasaki H, Kobayashi Y, Nakashima Y, Moriyama S, Yukiue H, Kaji M, Kiriyama M, Fukai I, Yamakawa Y and Fujii Y . (2002). Jpn. J. Clin. Oncol., 32, 85–89.

  • Skonier J, Neubauer M, Madisen L, Bennett K, Plowman GD and Purchio AF . (1992). DNA Cell Biol., 11, 511–522.

  • Smiraglia DJ and Plass C . (2002). Oncogene, 21, 5414–5426.

  • Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ and Wakefield LM . (1998). Nat. Med., 4, 802–807.

  • Thiery JP . (2002). Nat. Rev. Cancer, 2, 442–454.

  • Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, Baylin SB and Issa JP . (1999). Cancer Res., 59, 2307–2312.

  • Toyota M and Issa JP . (2002). Methods Mol. Biol., 200, 101–110.

  • Verrecchia F and Mauviel A . (2002). J. Invest. Dermatol., 118, 211–215.

  • Zhu WG, Dai Z, Ding H, Srinivasan K, Hall J, Duan W, Villalona-Calero MA, Plass C and Otterson GA . (2001a). Oncogene, 20, 7787–7796.

  • Zhu WG, Lakshmanan RR, Beal MD and Otterson GA . (2001b). Cancer Res., 61, 1327–1333.

Download references

Acknowledgements

We thank Michael Weinstein for help and discussions and Kristin Becknell for editorial assistance. This work was supported in part by Grants P30 CA16058, RO1 CA93548 and R01 DE13123 (CP). This work is also supported by a V-Foundation translational award to CP, a Leukemia and Lymphoma Society Scholar.

Author information

Authors and Affiliations

  1. Department of Molecular Virology, Human Cancer Genetics Program, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210, OH, USA

    Zunyan Dai, Anthony P Popkie, Cynthia D Timmers, Aparna Raval, Carl D Morrison, Herbert Auer, Gustavo W Leone & Christoph Plass

  2. Department of Pathology, The Ohio State University, Columbus, 43210, OH, USA

    Zunyan Dai & Carl D Morrison

  3. Department of Molecular Genetics, The Ohio State University, Columbus, 43210, OH, USA

    Anthony P Popkie & Gustavo W Leone

  4. Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University, Columbus, 43210, OH, USA

    Wei-Guo Zhu & Gregory A Otterson

  5. Department of Veterinary Biosciences and the Comprehensive Cancer Center, The Ohio State University, Columbus, 43210, OH, USA

    Sarah Tannehill-Gregg & Thomas Rosol

  6. Minneapolis VA Medical Center, 1 Veterans Drive, 111E, Minneapolis, 55417, MN, USA

    Robert A Kratzke & Gloria Niehans

  7. Department of Dermatology, University of Vienna, Vienna, 1090, Austria

    Stefan Amatschek

  8. Boehringer Ingelheim, Vienna, 1120, Austria

    Wolfgang Sommergruber

Authors
  1. Zunyan Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony P Popkie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei-Guo Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cynthia D Timmers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aparna Raval
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah Tannehill-Gregg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carl D Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Herbert Auer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert A Kratzke
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gloria Niehans
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefan Amatschek
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wolfgang Sommergruber
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gustavo W Leone
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas Rosol
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gregory A Otterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christoph Plass
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph Plass.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dai, Z., Popkie, A., Zhu, WG. et al. Bone morphogenetic protein 3B silencing in non-small-cell lung cancer. Oncogene 23, 3521–3529 (2004). https://doi.org/10.1038/sj.onc.1207441

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207441

Keywords

This article is cited by

Search

Advanced search

Quick links