Up-regulation of Kruppel-Like Factor 8 Promotes Tumor Invasion and Indicates Poor Prognosis for Hepatocellular Carcinoma
Up-regulation of Kruppel-Like Factor 8 Promotes Tumor Invasion and Indicates Poor Prognosis for Hepatocellular Carcinoma
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DOI：
10.1053/j.gastro.2010.08.004
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发表时间：
2010-12-01
期刊：
影响因子：
29.4
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Li, Jia-Chu;Yang, Xin-Rong;Fan, Jia
背景与目的：转录因子Kruppel样因子8（KLF8）在肿瘤的发生、生长和转移中发挥作用，但其在肝细胞癌（HCC）中的作用尚不清楚。方法：通过实时定量聚合酶链反应、免疫印迹和免疫化学分析来测量人 HCC 细胞系和肿瘤组织中 KLF8 的表达。在培养细胞和小鼠中观察到 KLF8 缺失或过度表达对 HCC 细胞的影响。通过微阵列分析研究了使用小干扰RNA降低KLF8水平的HCC细胞中基因表达模式的变化。通过对 314 名 HCC 患者的手术样本进行组织微阵列分析，验证了 KLF8 表达水平的临床意义。结果：KLF8 在高度转移性 HCC 细胞系和复发性 HCC 患者的样本中过度表达。在培养细胞中，KLF8上调促进细胞增殖和侵袭；抑制细胞凋亡； N-钙粘蛋白、波形蛋白和纤连蛋白下调；和上调 E-钙粘蛋白。在小鼠中，KLF8 的过度表达会增加 HCC 的进展和转移。微阵列分析表明，HCC 细胞中 KLF8 的减少会下调与肿瘤进展和转移有关的多个基因的表达。 KLF8 表达是总生存期 (P = .040) 和 HCC 复发时间 (P = .006) 的重要预测因子，并且与早期肿瘤复发相关 (P = .001)。结论：KLF8促进HCC细胞增殖和侵袭，抑制细胞凋亡，并诱导上皮间质转化。 KLF8 上调可用于指示接受 HCC 手术的患者预后不良或癌症早期复发。
BACKGROUND & AIMS: The transcription factor Kruppel-like factor 8 (KLF8) has a role in tumor development, growth, and metastasis, but its role in hepatocellular carcinoma (HCC) is not clear. METHODS: KLF8 expression in human HCC cell lines and tumor tissues was measured by quantitative real-time polymerase chain reaction, immunoblot, and immunochemical analyses. The effects of KLF8 depletion or overexpression in HCC cells were observed in cultured cells and in mice. Changes in gene expression patterns in HCC cells in which levels of KLF8 were reduced using small interfering RNA were investigated by microarray analysis. The clinical significance of KLF8 expression levels were validated using tissue microarray analysis of surgical samples from 314 HCC patients. RESULTS: KLF8 was overexpressed in highly metastatic HCC cell lines and in samples from patients with recurrent HCC. In cultured cells, KLF8 up-regulation promoted cell proliferation and invasion; inhibited apoptosis; down-regulated N-cadherin, vimentin, and fibronectin; and up-regulated E-cadherin. In mice, overexpression of KLF8 increased HCC progression and metastasis. Microarray analysis showed that reduction of KLF8 in HCC cells down-regulated expression of multiple genes involved in tumor progression and metastasis. KLF8 expression was a significant predictor of overall survival (P = .040) and time to HCC recurrence (P = .006) and was associated with early tumor recurrence (P = .001). CONCLUSIONS: KLF8 promotes HCC cell proliferation and invasion, inhibits apoptosis, and induces the epithelial-to-mesenchymal transition. KLF8 up-regulation might be used to indicate poor prognosis or early recurrence of cancer in patients who have had surgery for HCC.