Dysregulated Krüppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma.
Dysregulated Krüppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma.
复制标题
DOI：
10.1053/j.gastro.2012.05.043
复制
发表时间：
2012-09
期刊：
影响因子：
29.4
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Li Q;Gao Y;Jia Z;Mishra L;Guo K;Li Z;Le X;Wei D;Huang S;Xie K
KRüppel-like factor4(KLF4)是一种可能的肿瘤抑制基因，但KLF4在肝细胞癌变过程中的功能状态和意义尚不清楚。在这项研究中，我们试图确定其异常信号和生物影响的临床意义和潜在机制。我们利用肝细胞癌组织芯片、分子生物学和动物模型对KLF4-维生素D受体(VDR)通路在人肝细胞癌中的激活和功能进行了研究。与正常肝组织相比，KLF4蛋白在原发性肝细胞癌，尤其是有淋巴结转移的肝组织中的表达降低或缺失。此外，KLF4在原发肿瘤中的表达缺失与生存不良显著相关，也是一个预后标志。大多数人肝细胞癌细胞系均表现出KLF4表达缺失或显著降低。启动子高甲基化导致KLF4表达下降。强制恢复KLF4的表达导致MET，并显著抑制细胞在体外的迁移、侵袭和生长，并显著抑制动物模型的肿瘤生长和转移。此外，VDR是KLF4的直接转录靶点，也是VDR启动子中与KLF4蛋白特异结合的两个KLF4结合位点。VDR表达的增加使维生素D对肿瘤生长的抑制作用增敏。新的KLF4-VDR通路在肝细胞癌的发生发展中起关键作用，其失控信号可能成为设计新的预防和治疗策略以控制肝癌的新的分子靶点。
Krüppel-like factor 4 (KLF4) is a putative tumor suppressor gene, however, the functional status and significance of KLF4 in hepatocellular carcinogenesis is unknown. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated signaling and biologic impact. We have used HCC tissue microarray and molecular biology and animal models to evaluate the activation and function of KLF4-Vitamin D Receptor (VDR) pathway in human HCC. KLF4 protein expression was decreased or lost in primary HCC and, in particular, lymph node metastases when compared with that in normal liver. Moreover, loss of KLF4 expression in the primary tumors was significantly associated with poor survival, and also a prognostic marker. Consistently, most human HCC cell lines exhibited loss of or a substantial decrease in KLF4 expression. Promoter hypermethylation contributed to the decreased KLF4 expression. Enforced restoration of KLF4 expression resulted in MET, and marked inhibition of cell migration, invasion and growth in vitro, and significantly attenuated tumor growth and metastasis in animal models. Moreover, VDR is a direct transcriptional target of KLF4 and two KLF4-binding sites in the VDR promoter bound specifically to KLF4 protein. Increased VDR expression sensitized the inhibitory effects of Vitamin D on tumor growth. The novel KLF4-VDR pathway plays a critical role in HCC development and progression and its deregulated signaling could be a promising new molecular target for designing novel preventive and therapeutic strategies to control this malignancy.
登录
查看更多内容
维生素D模拟seocalcitol的II期研究对无法手术的肝细胞癌患者。
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Villanueva A;Minguez B;Forner A;Reig M;Llovet JM
通讯作者：
Llovet JM
影响因子：
29.4
作者：
Laurent-Puig, P;Legoix, P;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
16
作者：
Shah, S;Islam, N;Byers, SW
通讯作者：
Byers, SW
影响因子：
3.6
作者：
Marik, Radharani;Fackler, MaryJo;Umbricht, Christopher B.
通讯作者：
Umbricht, Christopher B.