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Decreased expression of insulin-like growth factor binding protein 7 in human colorectal carcinoma is related to DNA methylation

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Abstract

Purpose

Insulin-like growth factor binding protein 7 (IGFBP-7) is considered a tumor suppressor in various cancers, but its role in colorectal cancer (CRC) is still uncertain. The aims of this study were to analyze the IGFBP-7 expression, and explore the mechanism responsible for the inactivation of IGFBP-7 in CRC.

Methods

mRNA expression was studied by RT-PCR and Northern blot analysis of cultured cells. Methylation status was analyzed by treatment with 5-aza-2′-deoxycytidine followed by sequencing of PCR products of sodium bisulfite-treated genomic DNA. IGFBP-7 protein expression was evaluated by immunohistochemistry (IHC) on tissue microarrays.

Results

mRNA expression was lost in six out of eight CRC cell lines as compared to normal colon cells. DNA methylation was found in the region of exon 1 and intron 1 of IGFBP-7. In tumor tissue, 107 out of 279 samples showed a negative expression of IGFBP-7 by IHC, which was significantly associated with poor prognosis. The analysis of 37 paired cancerous and normal mucosa samples confirmed the downregulation in the tumors, but revealed variable basal expression levels of IGFBP-7 in normal mucosal samples.

Conclusions

DNA methylation is a mechanism responsible for IGFBP-7 gene silencing providing a target for therapeutic intervention of this tumor suppressor gene.

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Acknowledgments

We appreciate that Dr Antje Siegert kindly provided us with the colon cancer cell line CX2. We thank Martina Eickmann for editorial assistance. This work was supported by a grant from the Deutsche Krebshilfe (grant 10-2210-Pe 4). Mrs Fei Ye received an Ernst from Leyden Fellowship of the Berlin Cancer Society during her stay at the Charité.

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Authors and Affiliations

  1. Institute of Pathology, Charité University Medicine Berlin—Campus Mitte, 10098, Berlin, Germany

    Fei Ye, Yuan Chen, Thomas Knösel, Karsten Schlüns, Manuela Pacyna-Gengelbach, Nicole Deutschmann & Iver Petersen

  2. Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310031, People’s Republic of China

    Maode Lai

  3. Institute of Pathology, Charité—Campus Mitte, Humboldt-University, 10098, Berlin, Germany

    Iver Petersen

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  1. Fei Ye
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  2. Yuan Chen
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  3. Thomas Knösel
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  4. Karsten Schlüns
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  5. Manuela Pacyna-Gengelbach
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  6. Nicole Deutschmann
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  7. Maode Lai
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  8. Iver Petersen
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Correspondence to Iver Petersen.

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Ye, F., Chen, Y., Knösel, T. et al. Decreased expression of insulin-like growth factor binding protein 7 in human colorectal carcinoma is related to DNA methylation. J Cancer Res Clin Oncol 133, 305–314 (2007). https://doi.org/10.1007/s00432-006-0171-z

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  • DOI: https://doi.org/10.1007/s00432-006-0171-z

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