Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness.
Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness.
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DOI：
10.1158/1078-0432.ccr-14-2437
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发表时间：
2015-02-15
期刊：
影响因子：
--
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Li Z;Jia Z;Gao Y;Xie D;Wei D;Cui J;Mishra L;Huang S;Zhang Y;Xie K
核转录因子维生素D受体(VDR)和叉头盒M1(FOXM1)信号转导异常在肿瘤的发生、发展中起重要作用。在这项研究中，我们试图确定VDR信号是否在胰腺导管腺癌(PDAC)中对FOXM1信号和发病机制产生因果影响。遗传和药理学方法被用来操纵VDR信号。VDR信号改变对PDAC细胞FOXM1表达和功能的影响通过分子和生化方法来确定，而对PDAC细胞生物学和致瘤性的影响则通过体外和体内实验系统来确定。通过对人类PDAC标本的分析，我们的研究结果的临床相关性得到了验证。人PDAC细胞和组织中VDR的低表达与FOXM1的高表达呈显著负相关。用1，25-二羟基维生素D3(1，25D)及其合成类似物EB1089和VDR转基因药物处理PDAC细胞，可显著抑制FOXM1信号转导，并显著抑制肿瘤的干性、生长和转移。机制上，1，25D和EB1089抑制FOXM1转录，降低核FOXM1蛋白表达水平。维生素D/VDR信号通路的失活是PDAC发生发展的关键因素，它通过上调FOXM1的表达和功能，增强PDAC细胞的干性、侵袭和转移。
Dysregulated signaling of nuclear transcription factors vitamin D receptor (VDR) and Forkhead box M1 (FOXM1) play important roles in transformation and tumorigenesis. In this study, we sought to determine whether VDR signaling causally impacted FOXM1 signaling in and pathogenesis of pancreatic ductal adenocarcinoma (PDAC). Genetic and pharmacologic approaches were used to manipulate VDR signaling. The impacts of altered VDR signaling on FOXM1 expression and function in PDAC cells was determined using molecular and biochemical methods, whereas that on PDAC cell biology and tumorigenicity was determined using in vitro and in vivo experimental systems. The clinical relevance of our findings was validated by analyzing human PDAC specimens. There was a striking inverse correlation between reduced expression of VDR and increased expression of FOXM1 in human PDAC cells and tissues. Treatment of PDAC cells with 1,25-dihydroxyvitamin D3 (1,25D), its synthetic analog EB1089, and VDR transgenics drastically inhibited FOXM1 signaling and markedly suppressed tumor stemness, growth and metastasis. Mechanistically, 1,25D and EB1089 repressed FOXM1 transcription and reduced the expression level of nuclear FOXM1 protein. Inactivation of Vitamin D/VDR signaling is a critical contributor to PDAC development and progression via elevated expression and function of FOXM1 and enhanced PDAC cell stemness, invasion, and metastasis.