Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

被引：6
作者：
Takagi, Keiko [1 ]
Midorikawa, Yutaka [1 ]
Takayama, Tadatoshi [1 ]
Abe, Hayato [1 ]
Fujiwara, Kyoko [2 ,3 ]
Soma, Masayoshi [2 ,4 ]
Nagase, Hiroki [5 ]
Miki, Toshio [6 ]
Fukuda, Noboru [7 ]
机构：
[1] Nihon Univ, Dept Digest Surg, Sch Med, Tokyo 1738610, Japan
[2] Nihon Univ, Dept Med, Div Gen Med, Sch Med, Tokyo 1018309, Japan
[3] Nihon Univ, Dept Anat, Sch Dent, Tokyo 1018310, Japan
[4] Kyoundo Hosp, Sasaki Fdn, Dept Med, Tokyo 1010062, Japan
[5] Chiba Canc Ctr Res Inst, Lab Canc Genet, Chiba 2608717, Japan
[6] Nihon Univ, Dept Physiol, Sch Med, Tokyo 1738610, Japan
[7] Nihon Univ, Dept Med, Div Nephrol Hypertens & Endocrinol, Sch Med, Tokyo 1738610, Japan
来源：
MOLECULES | 2020年 / 25卷 / 12期
关键词：
pyrrole-imidazole polyamide; TGF-beta; 1; liver cancer; cancer stem cell; novel candidate drug; GROWTH-FACTOR-BETA; HEPATOCELLULAR-CARCINOMA; STEM-CELLS; MESENCHYMAL TRANSITION; PROTEIN EXPRESSION; GENE; DNA; TRANSCRIPTION; METASTASIS; INHIBITION;
D O I：
10.3390/molecules25122883
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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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页数：12
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