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DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma.

ABSTRACT: 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 ?-catenin expression was decreased in DKK4 transfectants. In addition, expression levels of the ?-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.

SUBMITTER: Hirata H

PROVIDER: S-EPMC5871344 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma.

Hirata Hiroshi H Hinoda Yuji Y Majid Shahana S Chen Yi Y Zaman Mohd S MS Ueno Koji K Nakajima Koichi K Tabatabai Z Laura ZL Ishii Nobuhisa N Dahiya Rajvir R

Cancer 20101108 8

<h4>Background</h4>To the authors' knowledge, the functional significance of the Wnt antagonist dickkopf homolog 4 (DKK4) has not been investigated previously in renal cancer.<h4>Methods</h4>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 ...[more]

PMID: 21472712

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. AsPC1 and A13A cells were stably transfected with a lentivirus expressing mock shRNA or shRNA to GATA6. Each control/shRNA pair (total 4 samples) was analyzed by two-color microarray and the genes commonly dysregulated in both cell lines identified.

Dataset Information

DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma.

Publications

DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma.

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