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Epigenetic Silencing of Somatostatin in Gastric Cancer

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Abstract

Background

Somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, has potent antitumor and anti-secretory activity in several human cancers.

Aims

This study was performed to investigate the SST gene expression levels and possible epigenetic mechanisms that regulate expression of SST in gastric adenocarcinomas.

Methods

Quantitative real-time (RT)-PCR and quantitative bisulfite pyrosequencing were used to study primary gastric cancer tissue samples and cell lines.

Results

Quantitative RT-PCR analysis revealed down-regulation of the SST transcript in 93% of gastric carcinoma samples (30/32), compared with 21 normal samples (P < 0.001). Because of the presence of a large CpG island in the SST promoter, we next examined its promoter DNA methylation levels by use of quantitative bisulfite pyrosequencing. The results revealed a significant increase in SST promoter DNA methylation in tumor samples compared with normal samples (P < 0.05). Promoter DNA hypermethylation and silencing of SST was also detected in seven gastric cancer cell lines that we tested. To confirm the role of promoter DNA methylation as an epigenetic mechanism regulating SST expression, AGS gastric cancer cells were treated with 5-Aza-dc. This treatment led to reduction of promoter DNA methylation levels of SST accompanied by restoration of its mRNA expression.

Conclusions

Our results indicate that promoter DNA methylation levels play a critical role in regulating SST expression in gastric cancer. This finding provides a foundation for further studies on the role of SST in gastric carcinogenesis and its potential as a biomarker for gastric cancers.

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References

  1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–362.

    PubMed  Google Scholar 

  2. Hansson LE, Sparen P, Nyren O. Increasing incidence of carcinoma of the gastric cardia in Sweden from 1970 to 1985. Br J Surg. 1993;80:374–377.

    Article  CAS  PubMed  Google Scholar 

  3. Roder DM. The epidemiology of gastric cancer. Gastric Cancer. 2002;5(Suppl 1):5–11.

    Article  PubMed  Google Scholar 

  4. Hohenberger P, Gretschel S. Gastric cancer. Lancet. 2003;362:305–315.

    Article  PubMed  Google Scholar 

  5. Berardi R, Scartozzi M, Galizia E, Cascinu S. Adjuvant chemotherapy in gastric cancer. The italian experience and review of the literature. Suppl Tumori. 2003;2:S45–S47.

    PubMed  Google Scholar 

  6. Jones PA. Epigenetics in carcinogenesis and cancer prevention. Ann N Y Acad Sci. 2003;983:213–219.

    Article  CAS  PubMed  Google Scholar 

  7. Baylin SB, Ohm JE. Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 2006;6:107–116.

    Article  CAS  PubMed  Google Scholar 

  8. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–428.

    Article  CAS  PubMed  Google Scholar 

  9. Jin Z, Mori Y, Hamilton JP, et al. Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis. Cancer. 2008;112:43–49.

    Article  CAS  PubMed  Google Scholar 

  10. Mori Y, Cai K, Cheng Y, et al. A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer. Gastroenterology. 2006;131:797–808.

    Article  CAS  PubMed  Google Scholar 

  11. Liddle RA, Jirtle RL. Epigenetic silencing of genes in human colon cancer. Gastroenterology. 2006;131:960–962.

    Article  CAS  PubMed  Google Scholar 

  12. Reubi JC, Laissue JA. Multiple actions of somatostatin in neoplastic disease. Trends Pharmacol Sci. 1995;16:110–115.

    Article  CAS  PubMed  Google Scholar 

  13. El-Rifai W, Moskaluk CA, Abdrabbo M, et al. Gastric cancers overexpress s100a calcium binding proteins. Cancer Res. 2002;62:6823–6826.

    CAS  PubMed  Google Scholar 

  14. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–107.

    Article  CAS  PubMed  Google Scholar 

  15. Ou JN, Torrisani J, Unterberger A, et al. Histone deacetylase inhibitor trichostatin a induces global and gene-specific DNA demethylation in human cancer cell lines. Biochem Pharmacol. 2007;73:1297–1307.

    Article  CAS  PubMed  Google Scholar 

  16. Wu LP, Wang X, Li L, et al. Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both cpg and h3k9 methylation on the promoter. Mol Cell Biol. 2008;28:3219–3235.

    Article  CAS  PubMed  Google Scholar 

  17. Xiong Y, Dowdy SC, Podratz KC, et al. Histone deacetylase inhibitors decrease DNA methyltransferase-3b messenger rna stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells. Cancer Res. 2005;65:2684–2689.

    Article  CAS  PubMed  Google Scholar 

  18. Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG, Davidson NE. Synergistic activation of functional estrogen receptor (er)-alpha by DNA methyltransferase and histone deacetylase inhibition in human er-alpha-negative breast cancer cells. Cancer Res. 2001;61:7025–7029.

    CAS  PubMed  Google Scholar 

  19. Peng DF, Razvi M, Chen H, et al. DNA hypermethylation regulates the expression of members of the mu-class glutathione s-transferases and glutathione peroxidases in Barrett’s adenocarcinoma. Gut. 2009;58:5–15.

    Article  CAS  PubMed  Google Scholar 

  20. Lee OJ, Schneider-Stock R, McChesney PA, et al. Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett’s tumorigenesis. Neoplasia. 2005;7:854–861.

    Article  CAS  PubMed  Google Scholar 

  21. Deng D, El-Rifai W, Ji J, et al. Hypermethylation of metallothionein-3 cpg island in gastric carcinoma. Carcinogenesis. 2003;24:25–29.

    Article  CAS  PubMed  Google Scholar 

  22. Schneider BG, Peng DF, Camargo MC, Piazuelo MB, Sicinschi LA, Mera R, Romero-Gallo J, Delgado AG, Bravo LE, Wilson KT, Peek RM, Jr., Correa P, El-Rifai W: Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int J Cancer. 2010. doi:10.1002/ijc.25274.

  23. Eads CA, Lord RV, Wickramasinghe K, et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 2001;61:3410–3418.

    CAS  PubMed  Google Scholar 

  24. Clement G, Braunschweig R, Pasquier N, Bosman FT, Benhattar J. Alterations of the wnt signaling pathway during the neoplastic progression of Barrett’s esophagus. Oncogene. 2006;25:3084–3092.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Institute of Health grants R01CA93999, UL1 RR024975, and R25CA102209. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or Vanderbilt University.

Author information

Authors and Affiliations

  1. Department of Surgery, Meharry Medical College, Nashville, Tennessee, 37208, USA

    Kaya Jackson & Dana Marshal

  2. Department of Surgery, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue, Nashville, Tennessee, 37232, USA

    Mohammed Soutto, DunFa Peng, TianLing Hu & Wael El-Rifai

  3. Cancer Biology, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue, Nashville, Tennessee, 37232, USA

    Wael El-Rifai

  4. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue, Nashville, Tennessee, 37232, USA

    Wael El-Rifai

Authors
  1. Kaya Jackson
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  2. Mohammed Soutto
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  3. DunFa Peng
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  4. TianLing Hu
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  5. Dana Marshal
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  6. Wael El-Rifai
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Corresponding author

Correspondence to Wael El-Rifai.

Additional information

Kaya Jackson, Mohammed Soutto, and DunFa Peng contributed equally to this work.

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Jackson, K., Soutto, M., Peng, D. et al. Epigenetic Silencing of Somatostatin in Gastric Cancer. Dig Dis Sci 56, 125–130 (2011). https://doi.org/10.1007/s10620-010-1422-z

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  • DOI: https://doi.org/10.1007/s10620-010-1422-z

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