Nitric oxide production upregulates Wnt/β-catenin signaling by inhibiting Dickkopf-1.
Nitric oxide production upregulates Wnt/β-catenin signaling by inhibiting Dickkopf-1.
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DOI：
10.1158/0008-5472.can-13-1620
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发表时间：
2013-11-01
期刊：
影响因子：
11.2
通讯作者：
Geller DA
中科院分区：
文献类型：
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作者：
Du Q;Zhang X;Liu Q;Zhang X;Bartels CE;Geller DA
一氧化氮信号在癌症的发生中扮演着复杂的角色，部分原因是对其机制的不完全理解。在这项研究中，我们发现诱导型一氧化氮合酶(INOS)和Wnt/β-连环蛋白调节因子Dickkopf-1(DKK1)在人类癌症中的表达呈负相关。在人类肿瘤和动物模型中，诱导性一氧化氮(NO)合成通过负性调节DKK1基因表达而增加WNT/β-连环蛋白信号转导。人iNOS(HiNOS)和Dkk1基因在原发人结肠癌和乳腺癌以及Min(Apcmin/+)小鼠肠腺瘤中的表达呈负相关。不同途径产生的NO足以降低组成性DKK1的表达，增加结肠癌、乳腺癌细胞和原代人肝细胞中Wnt/β-catenin信号转导，从而激活Wnt靶基因的转录。这一作用可通过RNAi介导的iNOS沉默或iNOS抑制剂处理而逆转，iNOS抑制剂可恢复Dkk1的表达及其对Wnt信号的抑制作用。综上所述，我们的结果确定了一种以前未知的机制，即NO途径通过释放Wnt/β-Catenin信号促进癌症。这些发现进一步证明了NO促进人类癌症的证据，并加深了对致癌过程中复杂的控制Wnt/β-catenin信号的洞察。
Nitric oxide signaling plays complex roles in carcinogenesis, in part due to incomplete mechanistic understanding. In this study, we investigated our discovery of an inverse correlation in the expression of the inducible nitric oxide synthase (iNOS) and the Wnt/β-catenin regulator Dickkopf-1 (DKK1) in human cancer. In human tumors and animal models, induced nitric oxide (NO) synthesis increased Wnt/β-catenin signaling by negatively regulating DKK1 gene expression. Human iNOS (hiNOS) and DKK1 gene expression were inversely correlated in primary human colon and breast cancers, and in intestinal adenomas from Min (Apcmin/+) mice. NO production by various routes was sufficient to decrease constitutive DKK1 expression, increasing Wnt/β-catenin signaling in colon and breast cancer cells and primary human hepatocytes, thereby activating the transcription of Wnt target genes. This effect could be reversed by RNAi-mediated silencing of iNOS or treatment with iNOS inhibitors, which restored DKK1 expression and its inhibitory effect on Wnt signaling. Taken together, our results identify a previously unrecognized mechanism through which the NO pathway promotes cancer by unleashing Wnt/β-catenin signaling. These findings further the evidence that NO promotes human cancer and deepens insights in the complex control Wnt/β-catenin signaling during carcinogenesis.