Wnt Antagonist DICKKOPF-3 (Dkk-3) Induces Apoptosis in Human Renal Cell Carcinoma
Wnt Antagonist DICKKOPF-3 (Dkk-3) Induces Apoptosis in Human Renal Cell Carcinoma
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DOI：
10.1002/mc.20729
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发表时间：
2011-06-01
影响因子：
4.6
通讯作者：
Dahiya, Rajvir
中科院分区：
文献类型：
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作者：
Ueno, Koji;Hirata, Hiroshi;Dahiya, Rajvir
Wnt信号通路在大多数癌症中被激活，而Wnt拮抗剂基因被失活。然而，Wnt拮抗剂Dkk-3基因失活在肾细胞癌（RCC）中的功能意义和机制尚未见报道。在这项研究中，我们研究了潜在的表观遗传机制调节Dkk-3在肾细胞癌细胞中的表达，以及Dkk-3的表达是否影响细胞生长和凋亡。肾癌细胞中Dkk-3的表达受组蛋白修饰而非CpG岛DNA甲基化调控转染Dkk-3基因的肾癌细胞增殖受到明显抑制，凋亡受到明显促进。Dkk-3不抑制Wnt/β-catenin信号通路，但通过非经典JNK通路诱导肾癌细胞凋亡。用Dkk-3表达质粒转染肾癌细胞系后，p21、MDM-2和Puma基因的表达增加。Dkk-3过表达可诱导细胞发生G（0）/G（1）阻滞，同时p21表达增加。与对照组相比，裸鼠中稳定的Dkk-3转染细胞的生长减少。我们的数据首次表明Dkk-3的mRNA表达受组蛋白修饰的调节，并且Dkk-3通过调节细胞周期和凋亡途径抑制肾癌生长。(C)2011 Wiley-Liss，Inc.
The Wnt signaling pathway is activated in most cancers while Wnt antagonist genes are inactivated. However, the functional significance and mechanisms of inactivation of Wnt antagonist Dkk-3 gene in renal cell carcinoma (RCC) has not been reported. In this study, we examined potential epigenetic mechanisms regulating Dkk-3 expression in RCC cells and whether Dkk-3 expression affects cell growth and apoptosis. The expression of Dkk-3 is regulated by histone modification rather than CpG island DNA methylation in renal cancer cells. Renal cancer cell proliferation was significantly inhibited and apoptosis was promoted in Dkk-3 transfected renal cancer cells. Dkk-3 did not inhibit the Wnt/beta-catenin signaling pathway but induced apoptosis via the noncanonical JNK pathway in renal cancer cells. Expression of p21, MDM-2, and Puma genes were increased after transfecting RCC cell lines with a Dkk-3 expression plasmid. Overexpression of Dkk-3 inducedG(0)/G(1) arrest together with an increase in p21 expression. Growth of stable Dkk-3 transfected cells in nude mice was decreased compared to controls. Our data show for the first time that mRNA expression of Dkk-3 is regulated by histone modification and that Dkk-3 inhibits renal cancer growth through modulation of cell cycle and apoptotic pathways. (C) 2011 Wiley-Liss, Inc.