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The myc 3' wnt-responsive element suppresses colonic tumorigenesis.

ABSTRACT: Mutations in components of the Wnt/?-catenin signaling pathway are commonly found in colorectal cancers, and these mutations cause aberrant expression of genes controlled by Wnt-responsive DNA elements (WREs). While the c-Myc proto-oncogene (Myc) is required for intestinal phenotypes associated with pathogenic Wnt/?-catenin signaling in vivo, the WREs that control Myc expression in this setting have yet to be fully described. Previously, we demonstrated that the Myc 3' WRE was required for intestinal homeostasis and intestinal repair in response to damage. Here, we tested the role of the Myc 3' WRE in intestinal tumorigenesis using two independent mouse models. In comparison to Apc(Min/+) mice, Apc(Min/+) Myc 3' WRE(-/-) mice contained 25% fewer tumors in the small intestine. Deletion of the Myc 3' WRE(-/-) in the Apc(Min/+) background resulted in 4-fold more colonic tumors. In a model of colitis-associated colorectal cancer, the Myc 3' WRE suppressed colonic tumorigenesis, most notably within the cecum. Using chromatin immunoprecipitation and transcript analysis of purified colonic crypts, we found that the Myc 3' WRE is required for the transcriptional regulation of Myc expression in vivo. These results emphasize the critical role of the Myc 3' WRE in maintaining homeostatic Myc expression.

SUBMITTER: Konsavage WM

PROVIDER: S-EPMC3993608 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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The myc 3' wnt-responsive element suppresses colonic tumorigenesis.

Konsavage Wesley M WM Yochum Gregory S GS

Molecular and cellular biology 20140224 9

Mutations in components of the Wnt/β-catenin signaling pathway are commonly found in colorectal cancers, and these mutations cause aberrant expression of genes controlled by Wnt-responsive DNA elements (WREs). While the c-Myc proto-oncogene (Myc) is required for intestinal phenotypes associated with pathogenic Wnt/β-catenin signaling in vivo, the WREs that control Myc expression in this setting have yet to be fully described. Previously, we demonstrated that the Myc 3' WRE was required for intes ...[more]

PMID: 24567369

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Project description:BackgroundN-myc downstream regulated gene 1 (NDRG1) plays a role in a variety of biological processes including differentiation of osteoclasts. However, it is not known if and how NDRG1 regulates osteogenic differentiation of marrow stromal progenitor cells.MethodsGene expression profiling analysis was performed to study the expression level of Ndrg1 during osteogenic and adipogenic differentiation. Gain-of-function and/or loss-of function experiments were carried out to study the role of NDRG1 in the proliferation and differentiation of marrow stromal progenitor cells and the mechanism underlying the function was investigated. Finally, in vivo transfection of Ndrg1 siRNA was done and its effect on osteogenic and adipogenic differentiation in mice was explored.ResultsGene expression profiling analysis revealed that NDRG1 level was regulated during osteogenic and adipogenic differentiation of progenitor cells. The functional experiments demonstrated that NDRG1 negatively regulated the cell growth, and reciprocally modulated the osteogenic and adipogenic commitment of marrow stromal progenitor cells, driving the cells to differentiate toward adipocytes at the expense of osteoblast differentiation. Moreover, NDRG1 interacted with low-density lipoprotein receptor-related protein 6 (LRP6) in the stromal progenitor cells and inactivated the canonical Wnt/β-catenin signaling cascade. Furthermore, the impaired differentiation of progenitor cells induced by Ndrg1 siRNA could be attenuated when β-catenin was simultaneously silenced. Finally, in vivo transfection of Ndrg1 siRNA to the marrow of mice prevented the inactivation of canonical Wnt signaling in the BMSCs of ovariectomized mice, and ameliorated the reduction of osteoblasts on the trabeculae and increase of fat accumulation in the marrow observed in the ovariectomized mice.ConclusionThis study has provided evidences that NDRG1 plays a role in reciprocally modulating osteogenic and adipogenic commitment of marrow stromal progenitor cells through inactivating canonical Wnt signaling.

Dataset Information

The myc 3' wnt-responsive element suppresses colonic tumorigenesis.

Publications

The myc 3' wnt-responsive element suppresses colonic tumorigenesis.

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