Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells
Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells
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DOI：
10.1016/j.toxlet.2014.08.024
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发表时间：
2014-11-18
影响因子：
3.5
通讯作者：
Zhang, Jianping
中科院分区：
文献类型：
--
作者：
Jiang, Fei;Wang, Xingxing;Zhang, Jianping
肝细胞癌（HCC）是全球癌症相关死亡的第三大原因。由于肝细胞癌的转移和复发，目前治疗肝细胞癌的标准做法不太令人满意，这主要归因于血管生成。因此，抗血管生成治疗已成为HCC治疗的新途径。除了治疗白血病，三氧化二砷（As2O3）也抑制其他实体肿瘤，包括HCC。然而，As2O3在HCC细胞血管生成潜能中的作用尚不清楚。在我们目前的研究中，As2O3通过microRNA-491 （miR-491）介导的对MHCC97H和MHCC97L细胞中tgf - β /SMAD3/NF-kappa B信号通路的抑制，降低了血管生成能力。简而言之，在这些细胞中，As2O3通过dna去甲基化提高了miR-491的表达；miR-491靶向SMAD3-3'-UTR，降低SMAD3的表达/功能，导致NF-kappa B/IL-6/STAT-3信号通路失活；miR-491的敲低消除了as2o3诱导的对tgf - β /SMAD3/NF-kappa B通路、VEGF分泌和血管生成的抑制。通过了解As2O3抑制HCC细胞血管生成潜能的新机制，我们的研究将有助于设计未来的策略，将As2O3开发为潜在的化学预防剂，无论是单独使用还是与其他现有抗癌药物联合使用。2014爱思唯尔爱尔兰有限公司版权所有。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current standard practices for treatment of HCC are less than satisfactory because of metastasis and recurrence, which are primarily attributed to the angiogenesis. So, the anti-angiogenesis treatment has become the new approach for HCC therapy. In addition to treating leukemia, arsenic trioxide (As2O3) also suppresses other solid tumors, including HCC. However, the roles of As2O3 in the angiogenesis potential of HCC cells remain unclear. In our present study, As2O3 attenuated the angiogenic ability by the microRNA-491 (miR-491)-mediated inhibition of TGF-beta/SMAD3/NF-kappa B signal pathway in MHCC97H and MHCC97L cells. Briefly, in these cells, As2O3 improved the expression of miR-491 via DNA-demethylation; miR-491, which targeted the SMAD3-3'-UTR, decreased the expression/function of SMAD3, leading to the inactivation of NF-kappa B/IL-6/STAT-3 signaling; knockdown of miR-491 abolished the As2O3-induced inhibitions of the TGF-beta/SMAD3/NF-kappa B pathway, the VEGF secretion, and the angiogenesis. By understanding a novel mechanism whereby As2O3 inhibits the angiogenic potential in HCC cells, our study would help in the design of future strategies of developing As2O3 as a potential chemopreventive agent when used alone or in combination with other current anticancer drugs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.