Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells
Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells
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DOI：
10.3390/molecules25122883
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发表时间：
2020-06-01
期刊：
影响因子：
4.6
通讯作者：
Fukuda, Noboru
中科院分区：
文献类型：
--
作者：
Takagi, Keiko;Midorikawa, Yutaka;Fukuda, Noboru
合成的吡咯-咪唑（PI）聚酰胺以高亲和力和特异性结合在双螺旋DNA的小凹槽上，抑制相应基因的转录。在肝癌中，转化生长因子(TGF)- β的表达与肿瘤分级相关，高级别肝癌组织表达上皮-间质转化标志物。据报道，tgf - β 1通过将癌前细胞转化为癌症干细胞（CSCs）参与了癌症的发展。本研究旨在探讨靶向tgf - β 1的PI聚酰胺对肝癌细胞和csc生长及tgf - β 1表达的影响。我们分析了靶向人tgf - β 1启动子的PI聚酰胺GB1101给药后tgf - β 1的表达水平，并检测了其对细胞增殖、侵袭性和tgf - β 1 mRNA表达水平的影响。GB1101剂量依赖性降低HepG2和HLF细胞tgf - β 1 mRNA水平，抑制HepG2集落形成，并下调tgf - β 1 mRNA。虽然与未处理的对照细胞相比，GB1101没有明显抑制HepG2细胞的增殖，但GB1101显著抑制了HLF细胞的侵袭，HLF细胞高表达CD44 （CSCs的标志物）。此外，GB1101除抑制HLE和HLF细胞增殖外，还通过抑制tgf - β 1的表达，显著抑制HLF细胞球的形成。综上所述，GB1101降低肝癌细胞中tgf - β 1的表达，抑制细胞侵袭；因此，GB1101是一种治疗肝癌的新型候选药物。
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.