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 ar e antagonized by the transforming growth factor beta signaling pathway, Her e human TCF-3 has been cloned and characterized. Differential expression an alyses 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 gast ric cancer, The TCF-3 expression vector was transfected to gastric cancer c ell line MKN28 to establish stable transformants, Three independent MKN28 t ransformants overexpressing TCF-3 showed about 8-fold resistance to mitomyc in C (MMC; IC50, 2.4 mug/ml) compared with MKN28 vector transfectants (IC50 = 0.3 mug/ml). Among the 10 drug resistance-associated genes examined in t his study, the DT-diaphorase (DTD) gene was down-regulated in three MKN28 t ransformants overexpressing TCF-3, DTD mRNA was also down-regulated in prim ary gastric cancer with TCF-3 up-regulation, In addition, DTD protein was d own-regulated in three hIKN28 transformants overexpressing TCF-3 compared w ith hIKN28 vector transfectants. DTD is implicated in the activation of MMC in target cells, and DTD down-regulation explains MMC resistance. MMC resi stance induced by TCF-3 overexpression is probably due to DTD down-regulati on, which might provide a possible target for new therapy of drug-resistant gastric cancer.