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.

  • Oncogenomics
  • Published:

Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas

Oncogene volume 25, pages 959–968 (2006)Cite this article

Abstract

TSLC1 (tumor suppressor in lung cancer-1, IGSF4) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell–cell adhesion. TSLC1 is connected to the actin cytoskeleton by DAL-1 (differentially expressed in adenocarcinoma of the lung-1, EPB41L3) and it directly associates with MPP3, one of the human homologues of a Drosophila tumor suppressor gene, Discs large. Recent data suggest that aberrant promoter methylation is important for TSLC1 inactivation in lung carcinomas. However, little is known about the other two genes in this cascade, DAL-1 and MPP3. Thus, we investigated the expression and methylation patterns of these genes in lung cancer cell lines, primary lung carcinomas and nonmalignant lung tissue samples. By reverse transcription–polymerase chain reaction, loss of TSLC1 expression was observed in seven of 16 (44%) non-small-cell lung cancer (NSCLC) cell lines and in one of 11 (9%) small-cell lung cancer (SCLC) cell lines, while loss of DAL-1 expression was seen in 14 of 16 (87%) NSCLC cell lines and in four of 11 (36%) SCLC cell lines. By contrast, MPP3 expression was found in all tumor cell lines analysed. Similar results were obtained by microarray analysis. TSLC1 methylation was seen in 13 of 39 (33%) NSCLC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs. DAL-1 methylation was observed in 17 of 39 (44%) NSCLC cell lines, in three of 11 (27%) SCLC cell lines and in 147 of 268 (55%) primary NSCLCs. In tumors of NSCLC patients with stage II–III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease. A significant correlation between loss of expression and methylation of the genes in lung cancer cell lines was found. Overall, 65% of primary NSCLCs had either TSLC1 or DAL-1 methylated. Methylation of one of these genes was detected in 59% of NSCLC cell lines; however, in SCLC cell lines, methylation was much less frequently observed. The majority of nonmalignant lung tissue samples was not TSLC1 or DAL-1 methylated. Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2′-deoxycytidine. Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC.

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
Figure 4
Figure 5

Similar content being viewed by others

References

  • Anderson JM . (1996). Curr. Biol., 6, 382–384.

  • Burbee DG, Forgacs E, Zöchbauer-Müller S, Shivakumar L, Fong KM, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M and Minna JD . (2001). J. Natl. Cancer Inst., 93, 691–699.

  • Cavallaro U and Christofori G . (2001). Biochim. Biophys. Acta, 30, 39–45.

  • Charboneau AL, Singh V, Yu T and Newsham IF . (2002). Int. J. Cancer, 100, 181–188.

  • Clark SJ, Harrison J, Paul CL and Frommer M . (1994). Nucleic Acids Res., 22, 2990–2997.

  • Esteller M, Corn PG, Baylin SB and Herman JG . (2001). Cancer Res., 61, 3225–3229.

  • Fukami T, Fukuhara H, Kuramochi M, Maruyama T, Isogai K, Sakamoto M, Takamoto S and Murakami Y . (2003). Int. J. Cancer, 107, 53–59.

  • Fukuhara H, Kuramochi M, Nobukuni T, Fukami T, Saino M, Maruyama T, Nomura S, Sekiya T and Murakami Y . (2001). Oncogene, 20, 5401–5407.

  • Fukuhara H, Masvuda M, Yageta M, Fukami T, Kuramochi M, Maruyama T, Kitamura T and Murakami Y . (2003). Oncogene, 22, 6160–6165.

  • Girard L and Minna JD . (2005) (in preparation).

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

  • Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, Murakami Y and Imamura M . (2003). Cancer Res., 63, 6320–6326.

  • Kikuchi S, Yamada D, Fukami T, Masuda M, Sakurai-Yageta M, Williams YN, Maruyama T, Asamura H, Matsuno Y, Onizuka M and Murakami Y . (2005). Clin. Cancer Res., 11, 2954–2961.

  • Kittiniyom K, Mastronardi M, Roemer M, Wells WA, Greenberg ER, Titus-Ernstoff L and Newsham IF . (2004). Genes Chromosomes Cancer, 40, 190–203.

  • Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP, Pletcher M, Isomura M, Onizuka M, Kitamura T, Sekiya T, Reeves RH and Murakami Y . (2001). Nat. Genet., 27, 427–430.

  • Lam CL, Wong MP, Girard L, Chung LP, Chiu SW, Suen WS, Lam WK and Minna JD . (2005) (in preparation).

  • Li LC and Dahiya R . (2002). Bioinformatics, 18, 1427–1431.

  • Mao X, Seidlitz E, Truant R, Hitt M and Ghosh HP . (2004). Oncogene, 7, 7.

  • Masuda M, Yageta M, Fukuhara H, Kuramochi M, Maruyama T, Nomoto A and Murakami Y . (2002). J. Biol. Chem., 277, 31014–31019.

  • Murakami Y, Nobukuni T, Tamura K, Maruyama T, Sekiya T, Arai Y, Gomyou H, Tanigami A, Ohki M, Cabin D, Frischmeyer P, Hunt P and Reeves RH . (1998). Proc. Natl. Acad. Sci. USA, 95, 8153–8158.

  • Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y, Pollack J, Peyton M, Zou Y, Kurie JM, Dimaio JM, Milchgrub S, Smith AL, Souza RF, Gilbey L, Zhang X, Gandia K, Vaughan MB, Wright WE, Gazdar AF, Shay JW and Minna JD . (2004). Cancer Res., 64, 9027–9034.

  • Sambrook J, Fritsch EF and Maniatis T. . (1989). Molecular Cloning – A Laboratory Manual, 2 edn. Cold Spring Harbor Laboratory Press: New York.

    Google Scholar 

  • Songyang Z, Fanning AS, Fu C, Xu J, Marfatia SM, Chishti AH, Crompton A, Chan AC, Anderson JM and Cantley LC . (1997). Science, 275, 73–77.

  • Toyooka S, Maruyama R, Toyooka KO, McLerran D, Feng Z, Fukuyama Y, Virmani AK, Zöchbauer-Müller S, Tsukuda K, Sugio K, Shimizu N, Shimizu K, Lee H, Chen CY, Fong KM, Gilcrease M, Roth JA, Minna JD and Gazdar AF . (2003). Int. J. Cancer, 103, 153–160.

  • Toyooka S, Toyooka KO, Maruyama R, Virmani AK, Girard L, Miyajima K, Harada K, Ariyoshi Y, Takahashi T, Sugio K, Brambilla E, Gilcrease M, Minna JD and Gazdar AF . (2001). Mol. Cancer Ther., 1, 61–67.

  • Tran Y, Benbatoul K, Gorse K, Rempel S, Futreal A, Green M and Newsham I . (1998). Oncogene, 17, 3499–3505.

  • Tran YK, Bogler O, Gorse KM, Wieland I, Green MR and Newsham IF . (1999). Cancer Res., 59, 35–43.

  • Virmani AK, Rathi A, Zöchbauer-Müller S, Sacchi N, Fukuyama Y, Bryant D, Maitra A, Heda S, Fong KM, Thunnissen F, Minna JD and Gazdar AF . (2000). J. Natl. Cancer Inst., 92, 1303–1307.

  • Virmani AK, Tsou JA, Siegmund KD, Shen LY, Long TI, Laird PW, Gazdar AF and Laird-Offringa IA . (2002). Cancer Epidemiol. Biomarkers Prev., 11, 291–297.

  • Xiong Y, Dowdy SC, Podratz KC, Jin F, Attewell JR, Eberhardt NL and Jiang SW . (2005). Cancer Res., 65, 2684–2689.

  • Yageta M, Kuramochi M, Masuda M, Fukami T, Fukuhara H, Maruyama T, Shibuya M and Murakami Y . (2002). Cancer Res., 62, 5129–5133.

  • Zöchbauer-Müller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF and Minna JD . (2001a). Cancer Res., 61, 3581–3585.

  • Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF and Minna JD . (2001b). Cancer Res., 61, 249–255.

Download references

Acknowledgements

This study was supported by grants from the Austrian Federal Ministry of Education, Science and Culture (GZ 200.062/2-VI/1/2002), by the Medical-Scientific Fund of the Mayor of the Federal Capital Vienna, by an award from the ‘Fonds der Stadt Wien für Innovative Interdisziplinäre Krebsforschung’ and Lung Cancer SPORE P50 CA70907.

Author information

Authors and Affiliations

  1. Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria

    Gerwin Heller, Sonja Seidl, Christoph C Zielinski & Sabine Zöchbauer-Müller

  2. Center of Excellence in Clinical and Experimental Oncology, University Hospital, Vienna, Austria

    Gerwin Heller, Christoph C Zielinski & Sabine Zöchbauer-Müller

  3. Prince Charles Hospital, Brisbane, Australia

    Kwun M Fong

  4. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA

    Luc Girard, Adi F Gazdar & John D Minna

  5. Department of Thoracic Surgery, University Hospital, Vienna, Austria

    Adelheid End-Pfützenreuter & György Lang

  6. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

    Adi F Gazdar

  7. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    John D Minna

  8. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA

    John D Minna

Authors
  1. Gerwin Heller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kwun M Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luc Girard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sonja Seidl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adelheid End-Pfützenreuter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. György Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adi F Gazdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John D Minna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christoph C Zielinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sabine Zöchbauer-Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sabine Zöchbauer-Müller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heller, G., Fong, K., Girard, L. et al. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas. Oncogene 25, 959–968 (2006). https://doi.org/10.1038/sj.onc.1209115

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209115

Keywords

This article is cited by

Search

Advanced search

Quick links