Zic2 promotes tumor growth and metastasis via PAK4 in hepatocellular carcinoma
Zic2 promotes tumor growth and metastasis via PAK4 in hepatocellular carcinoma
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Zic2通过PAK4促进肝细胞癌中的肿瘤生长和转移
DOI：
10.1016/j.canlet.2017.05.018
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发表时间：
2017-08-28
期刊：
影响因子：
9.7
通讯作者：
Yun, Jing-Ping
中科院分区：
文献类型：
--
作者：
Lu, Shi-Xun;Zhang, Chris Zhiyi;Yun, Jing-Ping
转录因子的失调导致了癌细胞的无限生长。Zic2已被证明对人类癌症的发展至关重要。然而，其在肝细胞癌（HCC）中的作用尚不清楚。我们的数据显示，Zic2的表达从正常组织到癌组织再到转移组织逐渐增加。Zic2过表达促进了体外细胞的增殖和迁移，而Zic2敲低抑制了体内肿瘤的生长和转移。基因芯片结果显示PAK4是Zic2的潜在靶点。Zic2的敲除减少，而Zic2的再表达增加，PAK4的表达增加。ChIP和荧光素酶实验表明Zic2直接结合PAK4启动子并调节其活性。PAK4干扰通过调节Raf/MEK/ERK通路减弱zic2介导的细胞生长。在615名患者的队列中，Zic2与PAK4呈正相关，并与较差的总生存期和无病生存期相关。多因素分析显示，Zic2和PAK4是HCC预后不良的独立指标。此外，Zic2表达与miR-1271表达呈负相关。重新引入miR-1271减弱zic2促进细胞增殖和迁移。综上所述，我们的研究结果表明，新发现的miR-1271/Zic2/PAK4轴在HCC进展中起重要作用，可能作为HCC的潜在治疗靶点。(C) 2017 Elsevier B.V.版权所有
The dysregulation of transcription factors contributes to the unlimited growth of cancer cells. Zic2 has been shown to be crucial to the progression of human cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Our data showed that Zic2 expression gradually increased from normal to cancer to metastatic tissues. Zic2 overexpression promoted, whereas Zic2 knockdown inhibited, cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Gene microarray results indicated that PAK4 was a potential target of Zic2. The knockdown of Zic2 decreased, whereas Zic2 re-expression increased, the expression of PAK4. ChIP and luciferase assays indicated that Zic2 directly bound to the PAK4 promoter and modulated its activity. PAK4 interference attenuated Zic2-mediated cell growth via modulating the Raf/MEK/ERK pathway. In a cohort of 615 patients, Zic2 was positively correlated with PAK4 and associated with worse overall and disease-free survival. Multivariate analyses revealed that Zic2 and PAK4 were independent indicators of a poor outcome in HCC. In addition, Zic2 expression was inversely correlated with miR-1271 expression. Re-introduction of miR-1271 attenuated Zic2-promoted cell proliferation and migration. Taken together, our findings suggest that the newly identified miR-1271/Zic2/PAK4 axis plays an important role in HCC progression and may serve as a potential therapeutic target for HCC. (C) 2017 Elsevier B.V. All rights reserved.