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  • Original Paper
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Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation

Oncogene volume 24, pages 6249–6255 (2005)Cite this article

Abstract

Recently, the human SRBC (hSRBC) gene, a candidate tumor suppressor gene (TSG), has been mapped to the chromosomal region 11p15.5–p15.4 where frequent allele loss has been described in lung cancer. Aberrant methylation (referred to as methylation) of the promoter region of TSGs has been identified as an important mechanism for gene silencing. Loss of hSRBC protein expression occurs frequently in lung cancer cell lines and sodium bisulfite sequencing of the promoter region of hSRBC in several lung cancer cell lines suggested that methylation plays an important role in inactivating hSRBC. To determine the methylation status of hSRBC in a large collection of primary lung cancer samples, corresponding nonmalignant lung tissues and lung cancer cell lines (N=52), we designed primers for a methylation-specific PCR assay. Methylation was detected in 41% of primary non-small-cell lung cancers (NSCLC) (N=107) and in 80% of primary small-cell lung cancers (SCLC) (N=5), but was seen only in 4% of corresponding nonmalignant lung tissues (N=103). In all, 79% of lung cancer cell lines were methylated and the frequency of hSRBC methylation was significantly higher in SCLC (100%) than in NSCLC (58%) cell lines. Normal hSRBC protein expression was detected in only 18% of primary NSCLCs (N=93) by immunostaining and a significant association between loss of protein expression and methylation was found. hSRBC re-expression was observed after treatment of lung cancer cells with the demethylating agent 5-aza-2′-deoxycytidine. In addition, 45% of the 76 hSRBC immunostaining-negative NSCLCs did not have hSRBC promoter methylation, indicating that other mechanisms of hSRBC expression silencing also exist. Both hSRBC immunostaining and methylation results did not correlate with clinicopathological characteristics of these patients. Our findings suggest that hSRBC is a candidate TSG involved in lung cancer pathogenesis, where expression is frequently inactivated by methylation and other mechanisms.

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Acknowledgements

This work was supported by grants from the Austrian Science Foundation (J1658-MED, J1860-MED), the Austrian Federal Ministry of Education, Science and Culture (GZ 200.062/2-VI/1/2002), the Medical-Scientific Fund of the Mayor of the Federal Capital Vienna (project number 2089), Lung Cancer SPORE P50 CA70907, Department of Defense Grant DAMD170110422 and The Susan G Komen Foundation.

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Authors and Affiliations

  1. Clinical Division of Oncology, Department of Medicine I, University Hospital, Währinger Gürtel 18-20, Vienna, 1090, Austria

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

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

    Sabine Zöchbauer-Müller, Gerwin Heller & Christoph C Zielinski

  3. The Prince Charles Hospital, Brisbane, Australia

    Kwun M Fong

  4. Roswell Park Cancer Institute, Buffalo, NY, USA

    Joseph Geradts

  5. Sagres Discovery, Davis, CA, USA

    Xie Xu

  6. Department of Cardiothoracic Surgery, University Hospital, Vienna, Austria

    Adelheid End-Pfützenreuter & György Lang

  7. Department of Thoracic Surgery, Korányi National Institute for Pulmonology, Budapest, Hungary

    György Lang

  8. Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Adi F Gazdar & John D Minna

  9. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Adi F Gazdar

  10. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    John D Minna

  11. Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    John D Minna

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  1. Sabine Zöchbauer-Müller
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  2. Kwun M Fong
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  3. Joseph Geradts
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  4. Xie Xu
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  6. Adelheid End-Pfützenreuter
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  7. György Lang
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  9. Christoph C Zielinski
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  10. Adi F Gazdar
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  11. John D Minna
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Correspondence to Sabine Zöchbauer-Müller.

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Zöchbauer-Müller, S., Fong, K., Geradts, J. et al. Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. Oncogene 24, 6249–6255 (2005). https://doi.org/10.1038/sj.onc.1208775

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