Journal
ISCIENCE
Volume 24, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.102411
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Funding
- National Institutes of Health USA [RO1CA168670]
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Enhanced stemness in colorectal cancer is closely associated with the Wnt ligand DKK2, which plays a critical role in promoting tumor progression by increasing LGR5-expressing cells. DKK2 activates the proto-oncogene tyrosine-protein kinase Src through degrading HNF4 alpha 1 protein, contributing to the aggressiveness of colorectal cancer.
Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4 alpha 1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.
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