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

Sabine Zöchbauer-Müller, Kwun M. Fong, Joseph Geradts, Xie Xu, Sonja Seidl, Adelheid End-Pfützenreuter, György Lang, Gerwin Heller, Christoph C. Zielinski, Adi F. Gazdar, John D. Minna

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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.

Original languageEnglish (US)
Pages (from-to)6249-6255
Number of pages7
JournalOncogene
Volume24
Issue number41
DOIs
StatePublished - Sep 15 2005

Fingerprint

DNA Methylation
Tumor Suppressor Genes
Methylation
Lung Neoplasms
Cell Line
decitabine
Small Cell Lung Carcinoma
Genetic Promoter Regions
Non-Small Cell Lung Carcinoma
Lung
Gene Silencing
Alleles
Polymerase Chain Reaction

Keywords

  • Epigenetic
  • hSRBC
  • Lung cancer
  • Methylation-specific PCR
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. / Zöchbauer-Müller, Sabine; Fong, Kwun M.; Geradts, Joseph; Xu, Xie; Seidl, Sonja; End-Pfützenreuter, Adelheid; Lang, György; Heller, Gerwin; Zielinski, Christoph C.; Gazdar, Adi F.; Minna, John D.

In: Oncogene, Vol. 24, No. 41, 15.09.2005, p. 6249-6255.

Research output: Contribution to journalArticle

Zöchbauer-Müller, S, Fong, KM, Geradts, J, Xu, X, Seidl, S, End-Pfützenreuter, A, Lang, G, Heller, G, Zielinski, CC, Gazdar, AF & Minna, JD 2005, 'Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation', Oncogene, vol. 24, no. 41, pp. 6249-6255. https://doi.org/10.1038/sj.onc.1208775
Zöchbauer-Müller S, Fong KM, Geradts J, Xu X, Seidl S, End-Pfützenreuter A et al. Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. Oncogene. 2005 Sep 15;24(41):6249-6255. https://doi.org/10.1038/sj.onc.1208775
Zöchbauer-Müller, Sabine ; Fong, Kwun M. ; Geradts, Joseph ; Xu, Xie ; Seidl, Sonja ; End-Pfützenreuter, Adelheid ; Lang, György ; Heller, Gerwin ; Zielinski, Christoph C. ; Gazdar, Adi F. ; Minna, John D. / Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation. In: Oncogene. 2005 ; Vol. 24, No. 41. pp. 6249-6255.
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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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AU - Xu, Xie

AU - Seidl, Sonja

AU - End-Pfützenreuter, Adelheid

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