Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

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

doi:10.1016/j.isci.2021.102411

Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

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

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Article number	102411
Journal	iScience
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2021.102411
Publication status	Published - 2021 May 21

Keywords

Cancer
Cell Biology
Stem Cells Research

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2021.102411

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Shin, J. H., Jeong, J., Choi, J., Lim, J., Dinesh, R. K., Braverman, J., Hong, J. Y., Maher, S. E., Amezcua Vesely, M. C., Kim, W. J., Koo, J. H., Tang, W., Wu, D., Blackburn, H. N., Xicola, R. M., Llor, X., Yilmaz, O., Choi, J. M., & Bothwell, A. L. M. (2021). Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1. iScience, 24(5), [102411]. https://doi.org/10.1016/j.isci.2021.102411

Shin, JH, Jeong, J, Choi, J, Lim, J, Dinesh, RK, Braverman, J, Hong, JY, Maher, SE, Amezcua Vesely, MC, Kim, WJ, Koo, JH, Tang, W, Wu, D, Blackburn, HN, Xicola, RM, Llor, X, Yilmaz, O, Choi, JM & Bothwell, ALM 2021, 'Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1', iScience, vol. 24, no. 5, 102411. https://doi.org/10.1016/j.isci.2021.102411

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title = "Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1",

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.",

keywords = "Cancer, Cell Biology, Stem Cells Research",

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

note = "Funding Information: This work was supported by National Institutes of Health USA, RO1CA168670 (awarded to A.L.M.B).The authors would like to thank GouzelTokmulina and ZuzanaTobiasova for the FACS sorting. Publisher Copyright: {\textcopyright} 2021 The Authors",

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doi = "10.1016/j.isci.2021.102411",

language = "English",

volume = "24",

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AU - Shin, Jae Hun

AU - Jeong, Jaekwang

AU - Choi, Jungmin

AU - Lim, Jaechul

AU - Dinesh, Ravi K.

AU - Braverman, Jonathan

AU - Hong, Jun Young

AU - Maher, Stephen E.

AU - Amezcua Vesely, Maria C.

AU - Kim, Won Ju

AU - Koo, Ja Hyun

AU - Tang, Wenwen

AU - Wu, Dianqing

AU - Blackburn, Holly N.

AU - Xicola, Rosa M.

AU - Llor, Xavier

AU - Yilmaz, Omer

AU - Choi, Je Min

AU - Bothwell, Alfred L.M.

N1 - Funding Information: This work was supported by National Institutes of Health USA, RO1CA168670 (awarded to A.L.M.B).The authors would like to thank GouzelTokmulina and ZuzanaTobiasova for the FACS sorting. Publisher Copyright: © 2021 The Authors

PY - 2021/5/21

Y1 - 2021/5/21

N2 - 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.

AB - 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.

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KW - Stem Cells Research

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Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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