Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma.
Wnt/beta-catenin signaling activates microRNA-181 expression in hepatocellular carcinoma.
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DOI：
10.1186/2045-3701-1-4
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发表时间：
2011-01-18
影响因子：
7.5
通讯作者：
Wang XW
中科院分区：
文献类型：
--
作者：
Ji J;Yamashita T;Wang XW
肝细胞癌（Hepatocellular carcinoma，HCC）是一种异质性较强的恶性肿瘤，microRNAs与HCC的发生密切相关。我们最近鉴定了从甲胎蛋白（AFP）阳性HCC样品中分离的EpCAM（CD326）阳性细胞是肝癌干细胞（HepCSC）。EpCAM + AFP + HepCSC具有活化的Wnt/β-连环蛋白信号传导，所有四种microRNA-181家族成员的表达平行增加。我们假设Wnt/β-catenin信号传导在HCC中转录激活microRNA-181。通过western blot和定量逆转录-PCR分析，我们发现所有四种microRNA-181家族成员的表达与HCC细胞系中β-catenin的表达呈正相关。MicroRNA-181表达可在Wnt/β-连环蛋白信号传导激活后直接诱导，其包括Wnt10B过表达、LiCl抑制GSK 3 β信号传导或β-连环蛋白/Tcf4的强制表达。此外，通过诱导结肠腺瘤性息肉病（APC）表达或通过RNA干扰沉默β-连环蛋白，Wnt/β-连环蛋白信号转导失活后，microRNA-181表达受到抑制。此外，在microRNA-181a-2和microRNA-181b-2转录物的启动子区域中鉴定了7个推定的β-catenin/Tcf4结合位点。因此，我们用染色质免疫沉淀法发现Tcf4在体内与这些区域相互作用。综上所述，我们的研究结果表明，microRNA-181在HCC中被Wnt/β-catenin信号通路转录激活。
Hepatocellular carcinoma (HCC) is a malignant cancer with an observable heterogeneity and microRNAs are functionally associated with the tumorigenesis of HCC. We recently identified that EpCAM (CD326)-positive cells isolated from alpha-fetoprotein (AFP)-positive HCC samples are hepatic cancer stem cells (HepCSCs). EpCAM+AFP+ HepCSCs have an activated Wnt/β-catenin signaling with a parallel increased expression of all four microRNA-181 family members. We hypothesized that Wnt/β-catenin signaling transcriptionally activates microRNA-181s in HCC. Using both western blot and quantitative reverse transcriptase-PCR analyses, we found that the expression of all four microRNA-181 family members was positively correlated with β-catenin expression in HCC cell lines. MicroRNA-181 expression could be directly induced upon an activation of Wnt/β-catenin signaling, which includes Wnt10B overexpression, inhibition of GSK3β signaling by LiCl, or forced expression of β-catenin/Tcf4. Moreover, microRNA-181 expression was inhibited upon an inactivation of Wnt/β-catenin signaling by an induction of adenomatosis polyposis coli (APC) expression or silencing β-catenin via RNA interference. In addition, seven putative β-catenin/Tcf4 binding sites were identified in the promoter region of the microRNA-181a-2 and microRNA-181b-2 transcripts. Consistently, we found that Tcf4 interacted with these regions in vivo using chromatin immunoprecipitation assay. Taken together, our results demonstrate that microRNA-181s are transcriptionally activated by the Wnt/beta-catenin signaling pathway in HCC.
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影响因子：
29.4
作者：
Laurent-Puig, P;Legoix, P;Zucman-Rossi, J
通讯作者：
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DOI：
10.1073/pnas.0305855101
发表时间：
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