Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6.
Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6.
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Krüppel 样因子 4 通过激活肝细胞核因子 6 阻止肝细胞癌去分化和进展
DOI：
10.1158/1078-0432.ccr-15-0528
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发表时间：
2016-01-15
期刊：
影响因子：
--
通讯作者：
Peng Z
中科院分区：
文献类型：
--
作者：
Sun H;Tang H;Xie D;Jia Z;Ma Z;Wei D;Mishra L;Gao Y;Zheng S;Xie K;Peng Z
目的：肿瘤分化是肝细胞癌（HCC）的行为指标，也是HCC患者接受原位肝移植（奥尔特）的预后因素。然而，HCC分化的分子基础和调节HCC分化的潜在分子的预后价值尚不清楚。在这项研究中，我们确定了一个潜在的驱动途径，肝癌分化和再分化。实验设计：利用人体组织、分子和细胞生物学以及动物模型评估了Krüppel样因子4（KLF 4）和肝细胞核因子-6（HNF-6）在HCC分化中的调节和功能，并根据其对患者生存的影响确定其预后意义。结果：KLF 4和HNF 6在HCC中的表达水平呈正相关。KLF 4或HNF 6表达降低与高肝癌级别相关。低分化肝癌细胞KLF 4或HNF 6和分化相关标志物的表达低于高分化细胞。KLF 4和HNF 6的高表达可诱导低分化肝癌细胞分化。从机制上讲，KLF 4反式激活HNF-6表达。恢复HNF-6表达上调分化相关标志物的表达，抑制HCC细胞迁移和侵袭，而HNF-6敲低则相反。原发性HCC中KLF 4表达缺失与奥尔特后总生存率降低和无复发生存期缩短相关。KLF 4表达与米兰标准相结合可提高肝奥尔特后肝癌的诊断率。结论：KLF 4/HNF-6通路的异常调节驱动HCC的去分化和进展，并且当与米兰标准结合时，KLF 4是通过奥尔特治疗的HCC患者的准确分类的生物标志物。Clin Cancer Res; 22（2）; 502-12.©2015 AACR.
Purpose: Tumor differentiation is a behavioral index for hepatocellular carcinoma (HCC) and a prognostic factor for patients with HCC who undergo orthotopic liver transplantation (OLT). However, the molecular basis for HCC differentiation and prognostic value of the underlying molecules that regulate HCC differentiation are unclear. In this study, we defined a potential driver pathway for HCC differentiation and prognostication. Experimental Design: The regulation and function of Krüppel-like factor 4 (KLF4) and hepatocyte nuclear factor-6 (HNF-6) in HCC differentiation was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. Results: There was a direct relationship between the expression levels of KLF4 and HNF6 in HCC. Reduced KLF4 or HNF6 expression correlated with high HCC grade. Poorly differentiated HCC cells had lower expression of KLF4 or HNF6 and differentiation-associated markers than did well-differentiated cells. Elevated KLF4 of HNF6 expression induced differentiation of poorly differentiated hepatoma cells. Mechanistically, KLF4 trans-activated HNF-6 expression. Restored HNF-6 expression upregulated expression of differentiation-associated markers and inhibited HCC cell migration and invasion, whereas HNF-6 knockdown did the opposite. Loss of KLF4 expression in primary HCC correlated with reduced overall survival and shortened relapse-free survival durations after OLT. Combination of KLF4 expression and the Milan criteria improved prognostication for HCC after OLT. Conclusions: The dysregulated KLF4/HNF-6 pathway drives dedifferentition and progression of HCC, and KLF4 is a biomarker for accurate prognostication of patients with HCC treated by OLT when integrated with the Milan Criteria. Clin Cancer Res; 22(2); 502–12. ©2015 AACR.