Kruppel-like factor 4 modulates the migration and invasion of hepatoma cells by suppressing TIMP-1 and TIMP-2
Kruppel-like factor 4 modulates the migration and invasion of hepatoma cells by suppressing TIMP-1 and TIMP-2
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DOI：
10.3892/or.2015.3964
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发表时间：
2015-07-01
期刊：
影响因子：
4.2
通讯作者：
Chi, Chin-Wen
中科院分区：
文献类型：
--
作者：
Sung, Ming-Ta;Hsu, Hui-Tzu;Chi, Chin-Wen
Kruppel样因子4（KLF 4）在发育、干性和肿瘤发生中发挥重要作用;然而，有关KLF 4在肝细胞癌（HCC）中的详细功能的信息有限。本研究的目的是研究KLF 4在肝癌细胞转移中的功能作用。用慢病毒转导方法在高转移肝癌细胞中过表达并敲低KLF 4。KLF 4在HCC细胞中的过表达导致细胞迁移和侵袭的抑制。这些抑制作用与KLF 4上调金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2有关。用重组TIMP-1处理HCC细胞可降低其迁移能力。此外，髓过氧化物酶（MPO）-TIMP-1/TIMP-2灭活剂抵消KLF 4诱导的细胞迁移/侵袭抑制。因此，KLF 4基因敲低可下调TIMP-1和TIMP-2的表达，从而促进细胞的迁移和侵袭。此外，我们发现KLF 4通过调节E-cadherin和上皮-间质转化（EMT）相关蛋白如snail、vimentin和Bmil来调节细胞的迁移能力。这些结果一起首次证明KLF 4通过上调TIMP-1和TIMP-2在抑制HCC细胞的侵袭性中起重要作用。
Kruppel-like factor 4 (KLF4) plays important roles in development, sternness and tumorigenesis; however limited information is available on the detailed function of KLF4 in hepatocellular carcinoma (HCC). The objective of the present study was to examine the functional roles of KLF4 in the metastasis of HCC cells. KLF4 was overexpressed and knocked down by lentiviral transduction method in highly metastatic HCC cells. KLF4 overexpression in HCC cells led to inhibition of cell migration and invasion. These inhibitory effects were associated with the upregulation of tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 by KLF4. Treatment with recombinant TIMP-1 decreased the migratory ability of HCC cells. Moreover, myeloperoxidase (MPO)-TIMP-1/TIMP-2 inactivator counteracted the KLF4-induced inhibition of cell migration/invasion. Consistently, KLF4 knockdown in HCC cells downregulated TIMP-1 and TIMP-2 expression, consequently promoting cell migration and invasion. Furthermore, we found that KLF4 regulated E-cadherin and epithelial-mesenchymal transition (EMT)-related proteins such as snail, vimentin and Bmil to modulate the cell migration ability. These results together demonstrated for the first time that KLF4 plays an important role in inhibiting the aggressiveness of HCC cells via upregulation of TIMP-1 and TIMP-2.