Jagged1 expression regulated by Notch3 and Wnt/β-catenin signaling pathways in ovarian cancer.
Jagged1 expression regulated by Notch3 and Wnt/β-catenin signaling pathways in ovarian cancer.
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DOI：
10.18632/oncotarget.127
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Wang TL
中科院分区：
文献类型：
--
作者：
Chen X;Stoeck A;Lee SJ;Shih IeM;Wang MM;Wang TL
卵巢浆液性癌是一种高度侵袭性的肿瘤性疾病。我们以前的研究表明，Notch 3基因扩增和上调在许多卵巢浆液性癌和Notch通路的活性有助于耐药。在Notch 3的不同配体中，Jagged 1在卵巢癌中的表达最多，并且Notch 3通路的活性与Jagged 1在卵巢癌组织中的表达水平相关。在这项研究中，我们发现Jagged 1的表达依赖于Notch 3通路的激活。Notch 3或RBPjk（一种Notch信号传导中的关键Notch相互作用转录因子）的敲低抑制了卵巢癌细胞中Jagged 1的表达。此外，Jagged 1的表达上调后，在人卵巢表面上皮细胞异位表达的Notch 3胞内结构域和上调后，从Notch 3诱导小鼠分离的小鼠上皮细胞诱导。我们还发现，抑制Wnt/β-catenin信号传导减少了Jagged 1的表达，并且共同施用靶向Notch 3和β-catenin的shRNA比靶向任一单独基因减少了Jagged 1的表达。综上所述，我们的数据表明，在卵巢癌细胞中，Notch 3及其配体Jagged 1之间存在正调控环。此外，Wnt/β-catenin通路的激活也上调了Jagged 1。这两种机制都可能维持Notch 3信号在卵巢癌细胞中的作用，并有助于卵巢癌的发病机制。
Ovarian serous carcinoma is a highly aggressive neoplastic disease in women. Our previous studies have demonstrated Notch3 gene amplification and upregulation in many ovarian serous carcinomas and Notch pathway activity contributed to drug resistance. Among different Notch3 ligands, Jagged1 is most dominant in ovarian cancer, and Notch3 pathway activity correlated with Jagged1 expression level in ovarian carcinoma tissues. In this study, we found that Jagged1 expression depended on Notch3 pathway activation. Knockdown of either Notch3 or RBPjk, a Notchinteracting transcription factor critical in Notch signaling, suppressed Jagged1 expression in ovarian cancer cells. Moreover, Jagged1 expression was upregulated in human ovarian surface epithelial cells after ectopic expression of Notch3 intracellular domain and was upregulated in mouse epithelial cells isolated from Notch3-inducible mice after induction. We also found that inhibition of Wnt/β-catenin signaling reduced Jagged1 expression, and co-administration of shRNAs targeting both Notch3 and β-catenin reduced Jagged1 expression much more than targeting either individual gene. Taken together, our data suggested a positive regulatory loop between Notch3 and its ligand, Jagged1, in ovarian cancer cells. In addition, Wnt/β-catenin pathway activation also up-regulated Jagged1. Both mechanisms may sustain Notch3 signaling in ovarian cancer cells and contribute to the pathogenesis of ovarian carcinoma.
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DOI：
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发表时间：
2008-02-12
影响因子：
11.1
作者：
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DOI：
10.1073/pnas.0813221106
发表时间：
2009-04-14
影响因子：
11.1
作者：
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通讯作者：
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