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Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1 : Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4 alpha 1

Cited 9 time in Web of Science Cited 10 time in Scopus
Authors

Shin, Jae Hun; Jeong, Jaekwang; Choi, Jungmin; Lim, Jaechul; Dinesh, Ravi K.; Braverman, Jonathan; Hong, Jun Young; Maher, Stephen E.; Amezcua Vesely, Maria C.; Kim, WonJu; Koo, Ja-Hyun; Tang, Wenwen; Wu, Dianqing; Blackburn, Holly N.; Xicola, Rosa M.; Llor, Xavier; Yilmaz, Omer; Choi, Je-Min; Bothwell, Alfred L.M.

Issue Date
2021-05
Publisher
Cell Press
Citation
iScience, Vol.24 No.5, p. 102411
Abstract
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.
ISSN
2589-0042
URI
https://hdl.handle.net/10371/201124
DOI
https://doi.org/10.1016/j.isci.2021.102411
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