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Protein expression and promoter methylation of the candidate biomarker TCF21 in gastric cancer

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Transcription factor 21 (TCF21) has been identified as a candidate tumor suppressor at 6q23–q24 that is epigenetically inactivated in many types of human cancers. This study aimed to determine the expression of TCF21 mRNA and protein in gastric cancer cell lines and tissue specimens and then investigate the prognostic impact of TCF21 expression in gastric cancer and analyze the relationship between TCF21 expression and methylation level.

Methods

We used real-time PCR and immunohistochemical staining to detect the expression of TCF21 and used methylation-specific-PCR to determine the methylation status of TCF21 in gastric cancer samples and gastric cancer cell lines.

Results

The results showed that TCF21 expression level in gastric cancer samples was significantly lower than in normal adjacent tissue samples. The Kaplan–Meier survival analysis demonstrated that TCF21 was a significant prognosticator of cancer-specific survival (p = 0.001). Furthermore, the methylation level of TCF21 in gastric cancer samples was much higher than the samples in normal adjacent tissue. Treatment with the DNA methyltransferase inhibitor 5-Aza-2′-deoxy-cytidine can upregulate the expression of TCF21 in gastric cancer cells.

Conclusions

These results suggest that the low expression of TCF21 was an independent prognostic factor for poor survival in patients with gastric cancer. Aberrant methylation was an important reason for the downregulation of TCF21 and may be associated with tumorigenesis in gastric cancer.

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References

  • Anglim PP, Galler JS, Koss MN, Hagen JA, Turla S et al (2008) Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer. Mol Cancer 7:62. doi:10.1186/1476-4598-7-62

    Article  PubMed Central  PubMed  Google Scholar 

  • Arab K, Smith LT, Gast A, Weichenhan D, Huang JP et al (2011) Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma. Carcinogenesis 32:1467–1473

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baum B, Settleman J, Quinlan MP (2008) Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 19:294–308

    Article  CAS  PubMed  Google Scholar 

  • Bhandari RK, Sadler-Riggleman I, Clement TM (2011) Skinner MK (2011) Basic helix-loop-helix transcription factor TCF21 is a downstream target of the male sex determining gene SRY. PLoS One 6(e19935):17. doi:10.1371/journal.pone.0019935

    Google Scholar 

  • Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P et al (2011) TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics 6:1120–1130

    Article  CAS  PubMed  Google Scholar 

  • Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12:354–362

    PubMed Central  PubMed  Google Scholar 

  • Gopalakrishnan S, Van Emburgh BO, Robertson KD (2008) DNA methylation in development and human disease. Mutat Res 647:30–38

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34:D140–D144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39:305–318

    Article  CAS  PubMed  Google Scholar 

  • Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA et al (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  • Kiemer AK, Takeuchi K, Quinlan MP (2001) Identification of genes involved in epithelial-mesenchymal transition and tumor progression. Oncogene 20:6679–6688

    Article  CAS  PubMed  Google Scholar 

  • Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Richardson JA, Olson EN (1998) Capsulin: a novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs. Mech Dev 73:23–32

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Chang P, Richardson JA, Gan L, Weiler H et al (2000) The basic helix-loop-helix transcription factor capsulin controls spleen organogenesis. Proc Natl Acad Sci USA 97:9525–9530

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu JR, Bassel-Duby R, Hawkins A, Chang P, Valdez R et al (2002) Control of facial muscle development by MyoR and capsulin. Science 298:2378–2381

    Article  CAS  PubMed  Google Scholar 

  • Matsubara H, Takeuchi T, Nishikawa E, Yanagisawa K, Hayashita Y et al (2007) Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene 26:6099–6105

    Article  CAS  PubMed  Google Scholar 

  • Meuwissen R, Berns A (2005) Mouse models for human lung cancer. Genes Dev 19:643–664

    Article  CAS  PubMed  Google Scholar 

  • Miyazawa J, Mitoro A, Kawashiri S, Chada KK, Imai K (2004) Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res 64:2024–2029

    Article  CAS  PubMed  Google Scholar 

  • Prindull G, Zipori D (2004) Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 103:2892–2899

    Article  CAS  PubMed  Google Scholar 

  • Quaggin SE, Schwartz L, Cui S, Igarashi P, Deimling J et al (1999) The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis. Development 126:5771–5783

    CAS  PubMed  Google Scholar 

  • Richards KL, Zhang B, Sun M, Dong W, Churchill J et al (2011) Methylation of the candidate biomarker TCF21 is very frequent across a spectrum of early-stage nonsmall cell lung cancers. Cancer 117:606–617

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shivapurkar N, Stastny V, Xie Y, Prinsen C, Frenkel E et al (2008) Differential methylation of a short CpG-rich sequence within exon 1 of TCF21 gene: a promising cancer biomarker assay. Cancer Epidemiol Biomarkers Prev 17:995–1000

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith LT, Lin M, Brena RM, Lang JC, Schuller DE et al (2006) Epigenetic regulation of the tumor suppressor gene TCF21 on 6q23-q24 in lung and head and neck cancer. Proc Natl Acad Sci USA 103:982–987

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Su Z, Xia J, Zhao Z (2011) Functional complementation between transcriptional methylation regulation and post-transcriptional microRNA regulation in the human genome. BMC Genom 12(Suppl 5):S15

    Article  CAS  Google Scholar 

  • Tessema M, Belinsky SA (2008) Mining the epigenome for methylated genes in lung cancer. Proc Am Thorac Soc 5:806–810

    Article  PubMed Central  PubMed  Google Scholar 

  • Tessema M, Willink R, Do K, Yu YY, Yu W et al (2008) Promoter methylation of genes in and around the candidate lung cancer susceptibility locus 6q23-25. Cancer Res 68:1707–1714

    Article  CAS  PubMed  Google Scholar 

  • Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Weiss D, Basel T, Sachse F, Braeuninger A, Rudack C (2011) Promoter methylation of cyclin A1 is associated with human papillomavirus 16 induced head and neck squamous cell carcinoma independently of p53 mutation. Mol Carcinog 50:680–688

    Article  CAS  PubMed  Google Scholar 

  • Weiss D, Stockmann C, Schrödter K, Rudack C (2013) Protein expression and promoter methylation of the candidate biomarker TCF21 in head and neck squamous cell carcinoma. Cell Oncol 36:213–224

    Article  CAS  Google Scholar 

  • Welch DR, Rinker-Schaeffer CW (1999) What defines a useful marker of metastasis in human cancer? J Natl Cancer Inst 91:1351–1353

    Article  CAS  PubMed  Google Scholar 

  • Ye YW, Jiang ZM, Li WH, Li ZS, Han YH et al (2012) Down-regulation of TCF21 is associated with poor survival in clear cell renal cell carcinoma. Neoplasma 59:599–605

    Article  CAS  PubMed  Google Scholar 

  • Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW (2000) Metastasis-suppressor genes: a review and perspective on an emerging field. J Natl Cancer Inst 92:1717–1730

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Guo Y, Shang C, Song Y, Wu B (2012) miR-21 downregulated TCF21 to inhibit KISS1 in renal cancer. Urology 80:1298–1302

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Higher Specialized Research Fund from the Doctoral Program of the Ministry of Education of China (#20102104110001), the Liao ning Province science and technology plan project (#2013225021) and the Young Innovation and Development Foundation from the Fourth Affiliated Hospital of China Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Cancer Center, The Fourth Hospital of China Medical University, Shenyang, China

    Z. Yang & D. Q. Dai

  2. Department of Emergency Surgery, The Fourth Hospital of China Medical University, Shenyang, China

    Z. Yang & Q. Xie

  3. Department of Anesthesiology, The Fourth Hospital of China Medical University, Shenyang, China

    D. M. Li

  4. Department of Gastrointestinal Surgery, The Fourth Hospital of China Medical University, Chongshan East Road 4, Shenyang, 110032, Liaoning, China

    D. Q. Dai

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  1. Z. Yang
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  2. D. M. Li
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Correspondence to D. Q. Dai.

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Yang, Z., Li, D.M., Xie, Q. et al. Protein expression and promoter methylation of the candidate biomarker TCF21 in gastric cancer. J Cancer Res Clin Oncol 141, 211–220 (2015). https://doi.org/10.1007/s00432-014-1809-x

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  • DOI: https://doi.org/10.1007/s00432-014-1809-x

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