Wilms' tumor gene WT1 17AA(-)/KTS(-) isoform induces morphological changes and promotes cell migration and invasion in vitro
Wilms' tumor gene WT1 17AA(-)/KTS(-) isoform induces morphological changes and promotes cell migration and invasion in vitro
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DOI：
10.1111/j.1349-7006.2006.00169.x
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发表时间：
2006-04-01
期刊：
影响因子：
5.7
通讯作者：
Sugiyama, H
中科院分区：
文献类型：
--
作者：
Jomgeow, T;Oji, Y;Sugiyama, H
野生型Wilms肿瘤基因WT1在人类原发性白血病和多种实体癌中过表达。所有四种WT1亚型都在原发性癌症中表达，并且每一种都被认为具有不同的功能。然而，每种WT1亚型在癌细胞中的功能尚不清楚。本研究表明，WT1 17AA(-)/KTS（-）异构体的组成表达可诱导TYK-nu细胞发生以小细胞形状为特征的形态学变化。CP-r （TYK）卵巢癌细胞。在WT1 17AA(-)/KTS（-）异构体转导的TYK细胞中，与模拟载体转导的TYK细胞相比，细胞基质粘附受到抑制，细胞迁移和体外侵袭增强。WT1 17AA(-)/KTS（-）异构体的组成表达也引起了8种癌细胞系（1种胃癌、1种食管癌、2种乳腺癌和1种纤维肉瘤）的形态学改变。除了WT1 17AA(-)/KTS（-）异构体外，没有其他WT1异构体引起表型变化。在WT1 17AA(-)/KTS（-）亚型转导的TYK细胞中，α -肌动蛋白1和cofilin表达减少，gelsolin表达增加。相比之下，α -肌动蛋白1和cofilin的共表达或通过小干扰RNA敲低gelsolin的表达可使WT1 17AA(-)/KTS（-）亚型转导的TYK细胞恢复到与亲本TYK细胞相当的表型。这些结果表明，WT1 17AA(-)/KTS（-）异构体通过调节细胞骨架动力学发挥其致癌功能。目前的结果可能为WT1基因的信号通路及其致癌功能提供新的见解。
The wild-type Wilms' tumor gene WT1 is overexpressed in human primary leukemia and in a wide variety of solid cancers. All of the four WT1 isoforms are expressed in primary cancers and each is considered to have a different function. However, the functions of each of the WT1 isoforms in cancer cells remain unclear. The present study demonstrated that constitutive expression of the WT1 17AA(-)/KTS(-) isoform induces morphological changes characterized by a small-sized cell shape in TYK-nu.CP-r (TYK) ovarian cancer cells. In the WT1 17AA(-)/KTS(-) isoform-transduced TYK cells, cell-substratum adhesion was suppressed, and cell migration and in vitro invasion were enhanced compared to that in mock vector-transduced TYK cells. Constitutive expression of the WT1 17AA(-)/KTS(-) isoform also induced morphological changes in five (one gastric, one esophageal, two breast and one fibrosarcoma) of eight cancer cell lines examined. No WT1 isoforms other than the WT1 17AA(-)/KTS(-) isoform induced the phenotypic changes. A decrease in alpha-actinin 1 and cofilin expression and an increase in gelsolin expression were observed in WT1 17AA(-)/KTS(-) isoform-transduced TYK cells. In contrast, co-expression of alpha-actinin 1 and cofilin or knockdown of gelsolin expression by small interfering RNA restored WT1 17AA(-)/KTS(-) isoform-transduced TYK cells to a phenotype that was comparable to that of the parent TYK cells. These results indicated that the WT1 17AA(-)/KTS(-) isoform exerted its oncogenic functions through modulation of cytoskeletal dynamics. The present results may provide a novel insight into the signaling pathway of the WT1 gene for its oncogenic functions.