Jomgeow Tanyarat, Oji Yusuke, Tsuji Naoko, Ikeda Yoko, Ito Ken, Tsuda Asako, Nakazawa Tsutomu, Tatsumi Naoya, Sakaguchi Nao, Takashima Satoshi, Shirakata Toshiaki, Nishida Sumiyuki, Hosen Naoki, Kawakami Manabu, Tsuboi Akihiro, Oka Yoshihiro, Itoh Kazuyuki, Sugiyama Haruo
Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka 565-0871, Japan.
Cancer Sci. 2006 Apr;97(4):259-70. doi: 10.1111/j.1349-7006.2006.00169.x.
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.
野生型肾母细胞瘤基因WT1在人类原发性白血病和多种实体癌中过表达。WT1的四种异构体均在原发性癌症中表达，且每种异构体都被认为具有不同的功能。然而，WT1各异构体在癌细胞中的功能仍不清楚。本研究表明，WT1 17AA(-)/KTS(-)异构体的组成型表达可诱导TYK-nu.CP-r（TYK）卵巢癌细胞出现以小细胞形态为特征的形态变化。在转导了WT1 17AA(-)/KTS(-)异构体的TYK细胞中，细胞与基质的粘附受到抑制，与转导空载体的TYK细胞相比，细胞迁移和体外侵袭能力增强。WT1 17AA(-)/KTS(-)异构体的组成型表达还在检测的8种癌细胞系中的5种（1种胃癌、1种食管癌、2种乳腺癌和1种纤维肉瘤）中诱导了形态变化。除WT1 17AA(-)/KTS(-)异构体外，其他WT1异构体均未诱导表型变化。在转导了WT1 17AA(-)/KTS(-)异构体的TYK细胞中，观察到α-辅肌动蛋白1和丝切蛋白表达降低，凝溶胶蛋白表达增加。相反，α-辅肌动蛋白1和丝切蛋白的共表达或小干扰RNA介导的凝溶胶蛋白表达下调可使转导了WT1 17AA(-)/KTS(-)异构体的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。本研究结果可能为WT1基因致癌功能的信号通路提供新的见解。
