Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer

Takayuki Fukui, Masashi Kondo, Genshi Ito, Osamu Maeda, Naohito Sato, Hiromu Yoshioka, Kohei Yokoi, Yuichi Ueda, Kaoru Shimokata, Yoshitaka Sekido

Research output: Contribution to journalArticle

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Abstract

Secreted frizzled related protein 1 (SFRP1) is an antagonist of the transmembrane frizzled receptor, a component of the Wnt signaling pathway, and has been suggested to be a candidate tumor suppressor in several human malignancies. Since SFRP1 is located at chromosome 8p11, where lung cancers also exhibit frequent allelic loss, we hypothesized that the inactivation of SFRP1 is also involved in lung carcinogenesis. To substantiate this, we performed mutational analysis of SFRP1 for 29 non-small-cell lung cancer (NSCLC) and 25 small-cell lung cancer (SCLC) cell lines, and expression analysis for the same cell lines. Although somatic mutations were not detected in the coding sequence, downregulation of SFRP1 was observed in 14 (48%) NSCLC and nine (36%) SCLC cell lines. We analysed epigenetic alteration of the SFRP1 promoter region and detected hypermethylation in 15 (52%) of 29 NSCLC cell lines, two (8%) of 25 SCLC cell lines, and 44 (55%) of 80 primary lung tumors. By comparing the methylation status with SFRP1 expression, we found a significant correlation between them. We also performed loss of heterozygosity (LOH) analysis and found that 15 (38%) of 40 informative surgical specimens had LOH in the SFRP1 gene locus. Furthermore, we performed colony formation assay of two NSCLC cell lines (NCI-H460 and NCI-H2009) and found the reduction of colony formation with SFRP1 transfection. In addition, we also detected that SFRP1 inhibits the transcriptional activity of β-catenin, which is thought to be a downstream molecule of SFRP1, with luciferase reporter assay. Our current studies demonstrated that the SFRP1 gene is frequently downregulated by promoter hypermethylation and suppresses tumor growth activity of lung cancer cells, which suggests that SFRP1 is a candidate tumor suppressor gene for lung cancer.

Original languageEnglish
Pages (from-to)6323-6327
Number of pages5
JournalOncogene
Volume24
Issue number41
DOIs
Publication statusPublished - 15-09-2005

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Non-Small Cell Lung Carcinoma
Cell Line
Loss of Heterozygosity
Small Cell Lung Carcinoma
Lung Neoplasms
frizzled related protein-1
Neoplasms
Down-Regulation
Frizzled Receptors
Catenins
Lung
Wnt Signaling Pathway
Tumor Suppressor Genes
Luciferases
Genetic Promoter Regions
Epigenomics
Methylation
Genes
Transfection
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Fukui, Takayuki ; Kondo, Masashi ; Ito, Genshi ; Maeda, Osamu ; Sato, Naohito ; Yoshioka, Hiromu ; Yokoi, Kohei ; Ueda, Yuichi ; Shimokata, Kaoru ; Sekido, Yoshitaka. / Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. In: Oncogene. 2005 ; Vol. 24, No. 41. pp. 6323-6327.
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abstract = "Secreted frizzled related protein 1 (SFRP1) is an antagonist of the transmembrane frizzled receptor, a component of the Wnt signaling pathway, and has been suggested to be a candidate tumor suppressor in several human malignancies. Since SFRP1 is located at chromosome 8p11, where lung cancers also exhibit frequent allelic loss, we hypothesized that the inactivation of SFRP1 is also involved in lung carcinogenesis. To substantiate this, we performed mutational analysis of SFRP1 for 29 non-small-cell lung cancer (NSCLC) and 25 small-cell lung cancer (SCLC) cell lines, and expression analysis for the same cell lines. Although somatic mutations were not detected in the coding sequence, downregulation of SFRP1 was observed in 14 (48{\%}) NSCLC and nine (36{\%}) SCLC cell lines. We analysed epigenetic alteration of the SFRP1 promoter region and detected hypermethylation in 15 (52{\%}) of 29 NSCLC cell lines, two (8{\%}) of 25 SCLC cell lines, and 44 (55{\%}) of 80 primary lung tumors. By comparing the methylation status with SFRP1 expression, we found a significant correlation between them. We also performed loss of heterozygosity (LOH) analysis and found that 15 (38{\%}) of 40 informative surgical specimens had LOH in the SFRP1 gene locus. Furthermore, we performed colony formation assay of two NSCLC cell lines (NCI-H460 and NCI-H2009) and found the reduction of colony formation with SFRP1 transfection. In addition, we also detected that SFRP1 inhibits the transcriptional activity of β-catenin, which is thought to be a downstream molecule of SFRP1, with luciferase reporter assay. Our current studies demonstrated that the SFRP1 gene is frequently downregulated by promoter hypermethylation and suppresses tumor growth activity of lung cancer cells, which suggests that SFRP1 is a candidate tumor suppressor gene for lung cancer.",
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Fukui, T, Kondo, M, Ito, G, Maeda, O, Sato, N, Yoshioka, H, Yokoi, K, Ueda, Y, Shimokata, K & Sekido, Y 2005, 'Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer', Oncogene, vol. 24, no. 41, pp. 6323-6327. https://doi.org/10.1038/sj.onc.1208777

Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. / Fukui, Takayuki; Kondo, Masashi; Ito, Genshi; Maeda, Osamu; Sato, Naohito; Yoshioka, Hiromu; Yokoi, Kohei; Ueda, Yuichi; Shimokata, Kaoru; Sekido, Yoshitaka.

In: Oncogene, Vol. 24, No. 41, 15.09.2005, p. 6323-6327.

Research output: Contribution to journalArticle

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T1 - Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer

AU - Fukui, Takayuki

AU - Kondo, Masashi

AU - Ito, Genshi

AU - Maeda, Osamu

AU - Sato, Naohito

AU - Yoshioka, Hiromu

AU - Yokoi, Kohei

AU - Ueda, Yuichi

AU - Shimokata, Kaoru

AU - Sekido, Yoshitaka

PY - 2005/9/15

Y1 - 2005/9/15

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