Department of Digestive Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.
Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo 101-8309, Japan.
Molecules. 2020 Jun 23;25(12):2883. doi: 10.3390/molecules25122883.
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)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 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-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 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-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.
合成的吡咯-咪唑（PI）聚酰胺与双链 DNA 的小沟具有高亲和力和特异性结合，并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-间充质转化标志物。TGF-β1 被报道通过将前癌细胞转化为癌症干细胞（CSC）而参与癌症的发展。本研究旨在评估靶向 TGF-β1 的 PI 聚酰胺对肝癌细胞和 CSC 生长及其 TGF-β1 表达的影响。我们分析了靶向人 TGF-β1 启动子的 PI 聚酰胺 GB1101 给药后 TGF-β1 表达水平，并研究了其对细胞增殖、侵袭和 TGF-β1 mRNA 表达水平的影响。GB1101 处理剂量依赖性地降低了 HepG2 和 HLF 细胞中的 TGF-β1 mRNA 水平，并抑制了与 TGF-β1 mRNA 下调相关的 HepG2 集落形成。尽管与未处理的对照细胞相比，GB1101 对 HepG2 细胞的增殖没有显著抑制作用，但 GB1101 显著抑制了高表达 CSC 标志物 CD44 的 HLF 细胞的侵袭。此外，GB1101 通过抑制 TGF-β1 表达，除了抑制 HLE 和 HLF 细胞的增殖外，还显著抑制了 HLF 细胞球体的形成。总之，GB1101 降低了肝癌细胞中的 TGF-β1 表达，并抑制了细胞侵袭；因此，GB1101 是治疗肝癌的一种新型候选药物。
