Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Gastroenterology. 2012 Sep;143(3):799-810.e2. doi: 10.1053/j.gastro.2012.05.043. Epub 2012 Jun 4.
BACKGROUND & AIMS: Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling.
We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway.
Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most human HCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastasis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D.
KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.
Krüppel 样因子 4（KLF4）是一种转录因子和潜在的肿瘤抑制因子。然而，关于其在肝细胞癌发生中的作用知之甚少。我们研究了失调的 KLF4 信号转导的临床意义、生物学效应和机制。
我们对肝细胞癌（HCC）组织进行了微阵列分析。我们使用分子生物学分析和动物模型来评估 KLF4-维生素 D 受体（VDR）途径的激活和功能。
与正常肝组织相比，原发性 HCC 样本中 KLF4 蛋白的表达降低或缺失，特别是淋巴结转移。原发性肿瘤中 KLF4 的缺失与生存时间缩短显著相关，并被确定为预后标志物。大多数人 HCC 细胞系中 KLF4 的水平降低或显著降低。在 HCC 细胞中外源表达 KLF4 上调了间质上皮转化（MET）的表达，并抑制了它们在体外的迁移、侵袭和增殖。当这些细胞被注射到小鼠体内时，与不表达 KLF4 的 HCC 细胞相比，肿瘤生长更慢，转移受到抑制。VDR 是 KLF4 的直接转录靶标；我们在 VDR 启动子中鉴定出 2 个与 KLF4 特异性结合的位点。VDR 的表达增加使肿瘤细胞对维生素 D 的抑制作用敏感。
KLF4 结合到 VDR 的启动子上调节其表达；在 HCC 细胞系和原发性肿瘤样本中，KLF4 的水平降低，而 VDR 的水平升高。在 HCC 细胞中表达 KLF4 使它们对 VD3 的抗增殖作用敏感。该途径可能被操纵以预防或治疗肝癌。
