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Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling

Oncogene volume 23, pages 1531–1538 (2004)Cite this article

Abstract

DNA hypomethylation is one of the major epigenetic alterations in human cancers. We have previously shown that genes identified as hypomethylated in pancreatic cancer are expressed in pancreatic cancer cell lines, but not in normal pancreatic ductal epithelium and can be reexpressed in nonexpressing cells using ‘epigenetic modifying agents’ such as DNA methyltransferase inhibitors. To identify additional targets for aberrant hypomethylation in pancreatic cancer, we used oligonucleotide microarrays to screen for genes that displayed expression patterns associated with hypomethylation. This analysis identified a substantial number of candidates including previously reported hypomethylated genes. A subset of eight genes were selected for further methylation analysis, and two cancer-related genes, maspin and S100P, were found to be aberrantly hypomethylated in a large fraction of pancreatic cancer cell lines and primary pancreatic carcinomas. Combined treatment with 5-aza-2′-deoxycytidie and trichostatin A resulted in synergistic induction of maspin and S100P mRNA in MiaPaCa2 cells where both genes were methylated. Furthermore, there was an inverse correlation between methylation and mRNA expression level for maspin and S100P in a large panel of pancreatic cancer cell lines. We also found a significant difference in the methylation patterns of maspin and two previously identified hypomethylated genes (trefoil factor 2 and lipocalin 2) between pancreatic and breast cancer cell lines, suggesting cancer-type specificity for some hypomethylation patterns. Thus, our present results confirm that DNA hypomethylation is a frequent epigenetic event in pancreatic cancer, and suggest that gene expression profiling may help to identify potential targets affected by this epigenetic alteration.

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Abbreviations

5Aza-dC:

5-aza-2′-deoxycytidine

TSA:

trichostatin A

MSP:

methylation-specific PCR

RT–PCR:

reverse transcription–PCR

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Acknowledgements

This work was supported by the SPORE in Gastrointestinal Malignancies (CA62924), the Grant CA90709, and the Michael Rolfe Foundation. We thank Dr Scott E Kern (The Johns Hopkins Medical Institutions, Baltimore, MD, USA) for providing the DNA samples from pancreatic cancer xenografts and Dr Mieke Schutte (University Hospital Rotterdam, The Netherlands) for providing DNA samples from breast cancer cell lines.

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Norihiro Sato, Noriyoshi Fukushima, Hiroyuki Matsubayashi & Michael Goggins

  2. Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Michael Goggins

  3. Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Michael Goggins

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  1. Norihiro Sato
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Correspondence to Michael Goggins.

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Sato, N., Fukushima, N., Matsubayashi, H. et al. Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling. Oncogene 23, 1531–1538 (2004). https://doi.org/10.1038/sj.onc.1207269

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