Mitomycin C resistance induced by TCF-3 overexpression in gastric cancer cell line MKN28 is associated with DT-diaphorase down-regulation.
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.
Sagara
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Genetics and Cell Biology Section, Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Katoh
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M
D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D024002:HMGB Proteins; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D024002:HMGB Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone)