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

Oncogene volume 24, pages 6323–6327 (2005)Cite this article

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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Acknowledgements

We acknowledge the assistance of Dr Adi F Gazdar for the lung cancer cell lines, and Dr Bert Vogelstein for providing the pGL3-OT and pGL3-OF. We also thank Dr Koichi Fujita and Dr Norio Mukoyama for the surgical specimens and Ms Hiroko Kaga for skillful technical assistance. This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Clinical Preventive Medicine, Nagoya University School of Medicine, Nagoya, 466-8550, Japan

    Takayuki Fukui, Genshi Ito, Osamu Maeda, Naohito Sato & Yoshitaka Sekido

  2. Department of Thoracic Surgery, Nagoya University School of Medicine, Nagoya, 466-8550, Japan

    Takayuki Fukui, Naohito Sato, Hiromu Yoshioka, Kohei Yokoi & Yuichi Ueda

  3. Department of Respiratory Medicine, Nagoya University School of Medicine, Nagoya, 466-8550, Japan

    Masashi Kondo, Genshi Ito & Kaoru Shimokata

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  1. Takayuki Fukui
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  2. Masashi Kondo
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Correspondence to Yoshitaka Sekido.

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Fukui, T., Kondo, M., Ito, G. et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24, 6323–6327 (2005). https://doi.org/10.1038/sj.onc.1208777

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