Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression.
Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression.
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DOI：
10.1371/journal.pone.0043593
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chen YW
中科院分区：
文献类型：
--
作者：
Lin ZS;Chu HC;Yen YC;Lewis BC;Chen YW
KRüppel-like factor4(KLF4)是一种锌指转录因子，在肿瘤的分化和发病机制中起重要作用。KLF4在不同的肿瘤类型中被认为是癌基因或肿瘤抑制基因。然而，KLF4在肝细胞癌中的作用尚不清楚。在这里，我们证明了KLF4在小鼠肝癌细胞系中的强制表达减少了软琼脂中的锚定非依赖性生长以及细胞在体外的迁移和侵袭活动。异位表达KLF4可损害皮下肿瘤生长和体内肺定植。相比之下，KLF4基因敲除促进了肝癌细胞的迁移。有趣的是，KLF4的异位表达改变了小鼠肝癌细胞的形态，使其具有更具上皮性的表型。与此相关的是，我们发现在表达KLF4的细胞中，关键的上皮间充质转化(EMT)相关转录因子Slug的表达显著下调。染色质免疫沉淀(ChIP)和荧光素酶报告分析表明，KLF4能够结合和抑制Slug启动子的活性。此外，异位表达的SLUG部分逆转了KLF4介导的表型。对Oncomine的公共微阵列数据库的分析表明，在4个数据集中，与正常肝组织相比，人肝细胞癌组织中KLF4的表达减少了，这与肝癌中肿瘤抑制因子的作用是一致的。通过定量逆转录聚合酶链式反应(qRT-PCR)，我们发现KLF4在50%的肝细胞癌组织中表达降低。重要的是，在肝细胞癌组织中发现KLF4和Slug的表达呈负相关。我们的数据表明，KLF4在肝癌细胞中发挥肿瘤抑制作用，部分是通过抑制Slug转录。
Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays an important role in differentiation and pathogenesis. KLF4 has been suggested to act as an oncogene or tumor suppressor in different tumor types. However, the role of KLF4 in hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrate that forced expression of Klf4 in murine HCC cell lines reduced anchorage-independent growth in soft agar as well as cell migration and invasion activities in vitro. Ectopic Klf4 expression impaired subcutaneous tumor growth and lung colonization in vivo. By contrast, Klf4 knockdown enhanced HCC cell migration. Interestingly, ectopic expression of Klf4 changed the morphology of murine HCC cells to a more epithelial phenotype. Associated with this, we found that expression of Slug, a critical epithelial mesenchymal transition (EMT)-related transcription factor, was significantly down-regulated in Klf4-expressing cells. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays showed that Klf4 is able to bind and repress the activity of the Slug promoter. Furthermore, ectopic Slug expression partially reverts the Klf4-mediated phenotypes. Consistent with a role as a tumor suppressor in HCC, analysis of the public microarray databases from Oncomine revealed reduced KLF4 expression in human HCC tissues in comparison with normal liver tissues in 3 out of 4 data sets. By quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we found reduced KLF4 mRNA in 50% of HCC tissues. Importantly, an inverse correlation between the expression of KLF4 and SLUG was found in HCC tissues. Our data suggest that KLF4 acts as a tumor suppressor in HCC cells, in part by suppressing SLUG transcription.
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