Mitomycin C resistance induced by TCF-3 overexpression in gastric cancer cell line MKN28 is associated with DT-diaphorase down-regulation

Cancer Res. 2000 Nov 1;60(21):5959-62.


TCF transcription factors are mediators of the WNT signaling pathway and are antagonized by the transforming growth factor beta signaling pathway. Here human TCF-3 has been cloned and characterized. Differential expression analyses of TCF genes in gastric cancer revealed that TCF-1 was expressed in most cases of primary gastric cancer at almost the same level as in normal gastric mucosa and that TCF-3 was occasionally up-regulated in primary gastric cancer. The TCF-3 expression vector was transfected to gastric cancer cell line MKN28 to establish stable transformants. Three independent MKN28 transformants overexpressing TCF-3 showed about 8-fold resistance to mitomycin C (MMC; IC50, 2.4 microg/ml) compared with MKN28 vector transfectants (IC50 = 0.3 microg/ml). Among the 10 drug resistance-associated genes examined in this study, the DT-diaphorase (DTD) gene was down-regulated in three MKN28 transformants overexpressing TCF-3. DTD mRNA was also down-regulated in primary gastric cancer with TCF-3 up-regulation. In addition, DTD protein was down-regulated in three MKN28 transformants overexpressing TCF-3 compared with MKN28 vector transfectants. DTD is implicated in the activation of MMC in target cells, and DTD down-regulation explains MMC resistance. MMC resistance induced by TCF-3 overexpression is probably due to DTD down-regulation, which might provide a possible target for new therapy of drug-resistant gastric cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antibiotics, Antineoplastic / pharmacology*
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • DNA, Complementary / isolation & purification
  • DNA, Neoplasm / genetics
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • HMGB Proteins*
  • Humans
  • Mitomycin / pharmacology*
  • Molecular Sequence Data
  • NAD(P)H Dehydrogenase (Quinone) / biosynthesis*
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • Sequence Homology, Amino Acid
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • TCF Transcription Factors
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Transfection
  • Transformation, Genetic
  • Tumor Cells, Cultured


  • Antibiotics, Antineoplastic
  • DNA, Complementary
  • DNA, Neoplasm
  • HMGB Proteins
  • TCF Transcription Factors
  • TCF7L1 protein, human
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors
  • Mitomycin
  • NAD(P)H Dehydrogenase (Quinone)

Associated data

  • GENBANK/AB031046