Taraxasterol suppresses the growth of human liver cancer by upregulating Hint1 expression
Taraxasterol suppresses the growth of human liver cancer by upregulating Hint1 expression
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DOI：
10.1007/s00109-018-1652-7
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发表时间：
2018-07-01
影响因子：
4.7
通讯作者：
Xiao, Chunjie
中科院分区：
文献类型：
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作者：
Bao, Tianhao;Ke, Yang;Xiao, Chunjie
蒲公英甾醇具有有效的抗炎和抗肿瘤活性。然而，蒲公英甾醇对人肝癌生长的影响及其可能的机制尚不清楚。组氨酸三联体核苷酸结合蛋白1（Hint 1）是一种肿瘤抑制因子，其表达下调与癌症的发生有关。在这里，我们报告蒲公英甾醇治疗显着抑制细胞增殖和诱导细胞周期停滞在G 0/G1期和肝癌细胞凋亡，但不是在非肿瘤肝细胞。蒲公英甾醇可上调肝癌细胞Hint 1和Bax的表达，下调Bcl 2和cyclin D1的表达，并促进Hint 1启动子区的去甲基化。蒲公英甾醇的作用被Hint 1沉默所消除，并被Bax沉默、Bcl 2或细胞周期蛋白D1在HepG 2细胞中的过表达所部分减轻。此外，蒲公英甾醇口服给药不影响BALB/c小鼠的体重、尿蛋白水平和心脏、肝脏和肾脏形态，但有效抑制体内移植的SK-Hep 1肿瘤的生长。总的来说，我们证明蒲公英甾醇至少部分地通过增强Hint 1表达来调节Bax，Bcl 2和细胞周期蛋白D1的表达来抑制肝癌的生长。蒲公英甾醇可能是治疗人肝癌的候选药物。蒲公英甾醇抑制人肝癌细胞生长并诱导其凋亡。蒲公英甾醇通过促进Hint 1启动子的去甲基化增强Hint 1表达。蒲公英甾醇增加Hint 1水平以调节Bax，Bcl 2，蒲公英甾醇的作用被肝癌细胞中的Hint 1沉默所消除。蒲公英甾醇抑制皮下肿瘤细胞的生长，在小鼠体内植入肝癌。
Taraxasterol has potent anti-inflammatory and anti-tumor activity. However, the effect and potential mechanisms of Taraxasterol on the growth of human liver cancer have not been clarified. Histidine triad nucleotide-binding protein 1 (Hint1) is a tumor suppressor and its downregulated expression is associated with the development of cancer. Here, we report that Taraxasterol treatment significantly suppressed cell proliferation and induced cell cycle arrest at G0/G1 phase and apoptosis in liver cancer cells, but not in non-tumor hepatocytes. Furthermore, Taraxasterol upregulated Hint1 and Bax, but downregulated Bcl2 and cyclin D1 expression, accompanied by promoting the demethylation in the Hint1 promoter region in liver cancer cells. The effects of Taraxasterol were abrogated by Hint1 silencing and partially mitigated by Bax silencing, Bcl2 or cyclin D1 over-expression in HepG2 cells. Moreover, oral administration with Taraxasterol did not affect body weight, urinary protein levels, and the heart, liver, and kidney morphology in BALB/c mice but effectively inhibited the growth of implanted SK-Hep1 tumor in vivo. Collectively, we demonstrate that Taraxasterol inhibits the growth of liver cancer at least partially by enhancing Hint1 expression to regulate Bax, Bcl2, and cyclin D1 expression. Taraxasterol may be a drug candidate for the treatment of human liver cancer.Taraxasterol inhibits growth and induces apoptosis in human liver cancer cells.Taraxasterol enhances Hint1 expression by promoting demethylation in Hint1 promoter.Taraxasterol increases Hint1 levels to regulate Bax, Bcl2, and cyclinD1 expression.The effects of Taraxasterol are abrogated by Hint1 silencing in liver cancer cells.Taraxasterol inhibits the growth of subcutaneously implanted liver cancers in mice.