Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
Cancer. 2011 Apr 15;117(8):1649-60. doi: 10.1002/cncr.25666. Epub 2010 Nov 8.
To the authors' knowledge, the functional significance of the Wnt antagonist dickkopf homolog 4 (DKK4) has not been investigated previously in renal cancer.
The authors initially observed that the expression of DKK4 was significantly higher in renal cancer tissues compared with adjacent normal kidney tissues. To assess the function of DKK4, stable DKK4-transfected cells were established, and functional analyses were performed, including a T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter assay and tests for cell viability, colony formation, apoptosis, cell cycle, invasive capability, wound-healing capability, and in vivo tumor growth.
The relative TCF/LEF activity was significantly lower in DKK4-transfected cells compared with empty vector, and nuclear β-catenin expression was decreased in DKK4 transfectants. In addition, expression levels of the β-catenin downstream effector proteins cyclin D1 and c-Myc were decreased in DKK4 transfectants. However, greater invasiveness and migration were observed in stably transfected DKK4 cells. Increased growth of DKK4-transfected tumors also was observed in nude mice. Members of the Wnt noncanonical/c-Jun-NH2 kinase (JNK) signaling pathway also were effected, such as c-Jun, which had significantly increased expression and phosphorylation in DKK4-stable transfectants, and matrix metalloproteinase-2, which had significantly increased expression in DKK4-stable transfectants.
This is the first study to indicate that DKK4 expression is increased in renal cancer tissues and that DKK4 activates the noncanonical JNK signaling pathway while inhibiting the Wnt-canonical pathway.
据作者所知，先前尚未研究过 Wnt 拮抗剂 dickkopf 同源物 4（DKK4）在肾细胞癌中的功能意义。
作者最初观察到，与相邻正常肾组织相比，DKK4 在肾癌细胞组织中的表达明显更高。为了评估 DKK4 的功能，建立了稳定转染 DKK4 的细胞，并进行了功能分析，包括 T 细胞因子/淋巴增强因子（TCF/LEF）报告基因测定以及细胞活力、集落形成、凋亡、细胞周期、侵袭能力、伤口愈合能力和体内肿瘤生长的检测。
与空载体相比，DKK4 转染细胞中的相对 TCF/LEF 活性显着降低，并且 DKK4 转染细胞中的核 β-连环蛋白表达降低。此外，β-连环蛋白下游效应蛋白 cyclin D1 和 c-Myc 的表达水平在 DKK4 转染细胞中降低。然而，稳定转染 DKK4 细胞的侵袭和迁移能力增强。在裸鼠中也观察到 DKK4 转染肿瘤的生长增加。Wnt 非经典/c-Jun-NH2 激酶（JNK）信号通路的成员也受到影响，例如 c-Jun，其在 DKK4 稳定转染细胞中表达和磷酸化明显增加，以及基质金属蛋白酶-2，其在 DKK4 稳定转染细胞中的表达明显增加。
这是第一项表明 DKK4 表达在肾癌细胞组织中增加的研究，并且 DKK4 激活非经典 JNK 信号通路，同时抑制 Wnt 经典途径。
