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Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer.

Methods

Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9).

Results

A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD).

Conclusion

The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.

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Acknowledgments

This work was supported by the Foundation for Pathobiochemistry and Molecular Diagnostics, German Society for Clinical Chemistry and Laboratory Medicine e. V. (DGKL; Bonn, Germany) (grant to B.S.). Funding was restricted to personnel and non-personnel costs. M. Otto, R. Brigelius-Flohé and the Nestlé Ltd. Research Centre are acknowledged for providing cell lines LS174T, Caco-2 and HCEC, respectively. Thanks are given to Monika Haseloff for technical assistance.

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    Authors and Affiliations

    1. Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany

      Christian Gerecke, Bettina Scholtka, Yvonne Löwenstein, Isabel Fait & Burkhard Kleuser

    2. Department of Internal Medicine, Gastroenterology and Interventional Endoscopy, Vivantes-Klinikum im Friedrichshain, Berlin, Germany

      Uwe Gottschalk

    3. Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany

      Dorothee Rogoll & Ralph Melcher

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    1. Christian Gerecke
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    Correspondence to Burkhard Kleuser.

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    Christian Gerecke and Bettina Scholtka have contributed equally to this work.

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    Gerecke, C., Scholtka, B., Löwenstein, Y. et al. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J Cancer Res Clin Oncol 141, 2097–2107 (2015). https://doi.org/10.1007/s00432-015-1972-8

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    • DOI: https://doi.org/10.1007/s00432-015-1972-8

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