Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1
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1-s2.0-S2589004221003795-main.pdf
Description
Published version
Size
9.9 MB
Format
Unknown
Checksum (MD5)
8fc67de38c7c4639c552f9c9a1c67545
Author(s)
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
Date Issued
May 2021
Journal
iScience
Publisher
Elsevier BV
Version
Final published version
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 HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.isci.2021.102411
