Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells
Keiko Takagi | Yutaka Midorikawa | Tadatoshi Takayama | Hayato Abe | Kyoko Fujiwara | Masayoshi Soma | Hiroki Nagase | Toshio Miki | Noboru Fukuda
Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-&beta: expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-&beta:1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-&beta:1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-&beta:1 expression. We analyzed TGF-&beta:1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-&beta:1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-&beta:1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-&beta:1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-&beta:1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-&beta:1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-&beta:1 expression in liver cancer cells and suppressed cell invasion: therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.
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