BACKGROUND: To the authors' knowledge, the functional significance of the Wnt antagonist dickkopf homolog 4 (DKK4) has not been investigated previously in renal cancer. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: To the authors' knowledge, the functional significance of the Wnt antagonist dickkopf homolog 4 (DKK4) has not been investigated previously in renal cancer. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Jinhua Wang; Isere Kuiatse; Adrian V Lee; Jingxuan Pan; Armando Giuliano; Xiaojiang Cui Journal: Mol Cancer Res Date: 2010-02-09 Impact factor: 5.852
Authors: K Kawasaki; M Watanabe; M Sakaguchi; Y Ogasawara; K Ochiai; Y Nasu; H Doihara; Y Kashiwakura; N-h Huh; H Kumon; H Date Journal: Cancer Gene Ther Date: 2008-07-25 Impact factor: 5.987
Authors: Elizabeth Mazzio; Ramesh Badisa; Nzinga Mack; Shamir Cassim; Masa Zdralevic; Jacques Pouyssegur; Karam F A Soliman Journal: Cancer Genomics Proteomics Date: 2020 Sep-Oct Impact factor: 4.069