β-Catenin activates the growth factor endothelin-1 in colon cancer cells
β-Catenin activates the growth factor endothelin-1 in colon cancer cells
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DOI：
10.1038/sj.onc.1208237
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发表时间：
2005-01-20
期刊：
影响因子：
8
通讯作者：
Ren, B
中科院分区：
文献类型：
--
作者：
Kim, TH;Xiong, H;Ren, B
内皮素-1（EDN 1）是一种生长因子，通常由癌细胞产生，在肿瘤发生中起关键作用。然而，控制癌症中EDN 1表达的分子机制尚不清楚。β-连环蛋白通路的组成性激活是绝大多数结肠癌的发生原因。在这里，我们表明EDN 1基因在结肠癌细胞中直接受β-连环蛋白调控。EDN 1启动子内的特异性DNA元件是激活所必需的，并且在体内与β-连环蛋白的同源DNA结合伴侣TCF 4相关。β-连环蛋白信号传导的抑制导致EDN 1的表达降低，而β-连环蛋白信号传导的增强导致该基因的进一步激活。在80%的原发性人类结肠癌中，EDN 1表达显著升高，这与它是β-连环蛋白的直接靶点一致。此外，EDN 1能够拯救结肠癌细胞免于由抑制β-连环蛋白信号传导引起的生长停滞和凋亡，这暗示EDN 1在促进β-连环蛋白的致癌功能中的关键作用。这些结果表明EDN 1过表达是结肠癌的主要原因，并揭示了负责结肠癌肿瘤发生的遗传程序的进一步细节。
Endothelin-1 (EDN1) is a growth factor that is frequently produced by cancer cells and plays a critical role in tumorigenesis. However, the molecular mechanism controlling the expression of EDN1 in cancers is unknown. Constitutive activation of beta-catenin pathway is responsible for the initiation of the vast majority of colon cancers. Here we show that the EDN1 gene is directly regulated by beta-catenin in colon cancer cells. A specific DNA element within the EDN1 promoter is required for activation, and is associated with beta-catenin's cognate DNA binding partner, TCF4, in vivo. Inhibition of beta-catenin signaling results in lowered expression of EDN1, while enhancement of beta-catenin signaling leads to further activation of the gene. Significantly elevated EDN1 expression occurs in 80% of primary human colon cancers, consistent with it being a direct target of beta-catenin. Furthermore, EDN1 is able to rescue colon cancer cells from growth arrest and apoptosis resulting from inhibition of beta-catenin signaling, implicating a key role of EDN1 in promoting the oncogenic function of beta-catenin. These results indicate EDN1 overexpression as a major cause in colon cancers and reveal further details of the genetic programs responsible for tumorigenesis of colon cancers.