Sulforaphane Inhibits Liver Cancer Cell Growth and Angiogenesis
Sulforaphane Inhibits Liver Cancer Cell Growth and Angiogenesis
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DOI：
10.21767/2254-6081.100189
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Shinya Sato;K. Moriya;Masanori Furukawa;Soichiro Saikawa;T. Namisaki;Mitsuteru Kitade;H. Kawaratani;K. Kaji;Hiroaki Takaya;Naotaka Shimozato;Yasuhiko Sawada;K. Seki;K. Kitagawa;Takemi Akahane;A. Mitoro;Yasushi Okura;H. Yoshiji;J. Yamao
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文献类型：
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作者：
Shinya Sato;K. Moriya;Masanori Furukawa;Soichiro Saikawa;T. Namisaki;Mitsuteru Kitade;H. Kawaratani;K. Kaji;Hiroaki Takaya;Naotaka Shimozato;Yasuhiko Sawada;K. Seki;K. Kitagawa;Takemi Akahane;A. Mitoro;Yasushi Okura;H. Yoshiji;J. Yamao
萝卜硫素 (SFN) 对不同类型的癌症具有抑制作用。但其对肝癌的抑制作用尚不清楚。本研究旨在确定 SFN 治疗肝癌的治疗潜力，并探讨 SFN 抑制作用的功能机制。进行水溶性四唑盐 (WST-1) 测定，以评估 SFN 对人肝癌细胞系 HepG2 和 Huh-7 细胞增殖的体外影响。使用定量RT-PCR测定Nrf2靶基因和细胞周期相关基因的mRNA水平。为了评估SFN的体内抑制作用，我们将永生化肝癌细胞注射到BALB/c裸鼠中作为异种移植模型。肿瘤接种后每天口服 SFN，持续三十五天直至处死。两种细胞系中 HO-1、MRP2 和 NQO1 mRNA 上调证实了 SFN 诱导的 Nrf2 激活。在体外，SFN 通过下调 CCND1、CCNB1、CDK1 和 CDK2 以剂量依赖性方式显着抑制肝癌细胞增殖。在体内研究中，通过 Ki67 免疫组织化学分析证实，在实验结束时，通过抑制肿瘤细胞增殖，SFN 的施用显着降低了皮下肿瘤负荷。在这些 SFN 处理的异种移植肿瘤中，CCND1、CCNB1、CDK1 和 CDK2 的 mRNA 水平也有所降低。此外，CD34免疫染色表明，SFN处理的异种移植肿瘤中瘤内新血管形成明显减弱。 SFN 对人肝癌细胞具有抑制作用，并具有抗血管生成活性。该研究的早期版本已在 2017 年 10 月的 AASLD 肝脏学习会议上提出。
Sulforaphane (SFN) exhibits inhibitory effects in different types of cancers. However, its inhibitory effect on liver cancer remains unknown. This study aimed to determine the therapeutic potential of SFN for the treatment of liver cancer and explore the functional mechanisms underlying the inhibitory effects of SFN. Water-Soluble Tetrazolium salt (WST-1) assay was performed to assess the in vitro effect of SFN on cell proliferation in the human liver cancer cell lines, HepG2 and Huh-7. The mRNA levels of Nrf2 target genes and cell cycle-related genes were determined using quantitative RT-PCR. For assessing the inhibitory effect of SFN in vivo, we injected immortalized liver cancer cells into BALB/c nude mice as a xenograft model. SFN was orally administrated daily after tumor inoculation and continued for thirty-five days until their sacrifices. Nrf2 activation, induced by SFN, was confirmed by mRNA upregulation of HO-1, MRP2, and NQO1 in both the cell lines. Significant inhibition of liver cancer cell proliferation by SFN was shown in vitro in a dose-dependent manner by the downregulation of CCND1, CCNB1, CDK1 and CDK2. In in vivo studies, the administration of SFN significantly reduced the subcutaneous tumor burdens at the end of experiments by suppressing tumor cell proliferation, confirmed by Ki67 immunohistochemical analysis. The mRNA levels of CCND1, CCNB1, CDK1 and CDK2 were also decreased in these SFNtreated xenograft tumors. Moreover, CD34 immunostaining elucidated that the intratumoral neovascularization was markedly attenuated in the SFN-treated xenograft tumors. SFN exerts inhibitory effect on human liver cancer cells with antiangiogenic activity. The earlier version of this study was presented at the meeting of AASLD Liver Learning on Oct 2017.