Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma
Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma
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Ikaros 和组蛋白脱乙酰酶下调 AZGP1 通过 PTEN/Akt 和 CD44s 通路促进肝细胞癌肿瘤进展
DOI：
10.1093/carcin/bgw125
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发表时间：
2017-02-01
期刊：
影响因子：
4.7
通讯作者：
Li, Jinjun
中科院分区：
文献类型：
--
作者：
Tian, Hua;Ge, Chao;Li, Jinjun
越来越多的证据表明，锌-α 2-糖蛋白（AZGP 1）与几种肿瘤类型的进展和预后相关。然而，关于AZGP 1在肝细胞癌（HCC）中的潜在分子机制知之甚少。在这项研究中，我们报告，转录因子Ikaros结合到AZGP 1启动子，并增加其在肝癌细胞中的表达。AZGP 1的下调与组蛋白去乙酰化有关。此外，通过组蛋白H4乙酰化介导的Ikaros启动子的反式激活和Ikaros介导的组蛋白H4乙酰化的反式激活的正反馈调节对于调节HCC细胞中AZGP 1的表达至关重要。此外，HCC患者血清AZGP 1水平低与预后不良相关。AZGP 1或重组AZGP 1蛋白的异位过表达在体外和体内抑制HCC细胞的增殖、迁移和侵袭，而AZGP 1表达的沉默导致细胞的增殖、迁移和侵袭增加。此外，我们发现AZGP 1通过调节PTEN/Akt和CD 44 s通路抑制细胞迁移和侵袭。总的来说，我们的研究结果揭示了AZGP 1在HCC中表达的分子机制，为肿瘤进展的潜在机制提供了新的见解。
Increasing evidence has shown that zinc-alpha2-glycoprotein (AZGP1) is associated with the progression and prognosis of several tumor types. However, little is known regarding the underlying molecular mechanisms of AZGP1 in hepatocellular carcinoma (HCC). In this study, we report that transcription factor Ikaros bound to the AZGP1 promoter and increased its expression in HCC cells. The downregulation of AZGP1 was associated with histone deacetylation in HCC. In addition, the positive feedback regulation via acetylation of histone H4-mediated transactivation of the Ikaros promoter and the Ikaros-mediated transactivation of the acetylation of histone H4 were crucial for regulating AZGP1 expression in HCC cells. Moreover, low serum AZGP1 level in HCC patients was associated with poor prognosis. The ectopic overexpression of AZGP1 or recombinant AZGP1 protein inhibited HCC cell proliferation, migration and invasion in vitro and in vivo, whereas silencing AZGP1 expression resulted in increased cell proliferation, migration and invasion in vitro. In addition, we found that AZGP1 inhibited cell migration and invasion through the regulation of the PTEN/Akt and CD44s pathways. Collectively, our findings revealed the molecular mechanism of AZGP1 expression in HCC, providing new insights into the mechanisms underlying tumor progression.