Transcription Factor AP2ε: A Potential Predictor of Chemoresistance in Patients With Gastric Cancer

Technol Cancer Res Treat. 2016 Apr;15(2):285-95. doi: 10.1177/1533034615577028. Epub 2015 Mar 25.


Chemotherapy is a mainstay of therapy for advanced gastric cancer (GC); however, owing to drug resistances, the effectiveness of chemotherapy is not satisfactory for some patients with GC. Therefore, identification of a marker that predicts treatment response is beneficial to patients. Hypermethylation of transcription factor activating enhancer-binding protein 2∊ (TFAP2E) has been implicated in chemotherapy resistance to fluorouracil-based chemotherapy in patients with colorectal cancer, but its role in GC is still unknown. In this study, we investigated TFAP2E as a predictor of treatment response in GC. We used methylation-sensitive high-resolution melting analysis to study the methylation of TFAP2E in 141 GC tissue specimens and 45 adjacent nontumor tissue specimens. In vitro experiments, we analyzed the expression and methylation of TFAP2E and to examine the sensitivity of GC cell lines to 5-fluorouracil (5-FU). The TFAP2E methylation occurred at a significantly higher incidence rate in tumor tissues compared to adjacent nontumor tissues (chi-square [χ2] = 38.919, P < .001). Hypermethylation of TFAP2E occurred more frequently in tumors with lower differentiation grades (P < .001) and was significantly associated with nonresponse to fluorouracil-based chemotherapy (P = .010). Hypermethylation was also associated with decreased expression of TFAP2E (P < .01) and nonresponse to 5-FU exposure in vitro (P < .001). Hypermethylation of TFAP2E was associated with lack of response to fluorouracil-based chemotherapy, indicating that it might be a potential predictor of treatment response in patients with GC.

Keywords: 5-fluorouracil; DNA methylation; TFAP2E; chemoresistance; gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / metabolism*
  • Cell Line, Tumor
  • DNA Methylation
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Female
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • ROC Curve
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / metabolism*
  • Transcription Factor AP-2 / metabolism*


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • TFAP2E protein, human
  • Transcription Factor AP-2
  • Deoxycytidine
  • Fluorouracil