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Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4 alpha 1
- Shin, Jae Hun;
- Jeong, Jaekwang;
- Choi, Jungmin;
- Lim, Jaechul;
- Dinesh, Ravi K.;
- ... Choi, Je-Min;
- 외 13명
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17초록
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.
키워드
- 제목
- Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4 alpha 1
- 저자
- Shin, Jae Hun; Jeong, Jaekwang; Choi, Jungmin; Lim, Jaechul; Dinesh, Ravi K.; Braverman, Jonathan; Hong, Jun Young; Maher, Stephen E.; Vesely, Maria C. Amezcua; 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.
- 발행일
- 2021-05
- 유형
- Article
- 저널명
- ISCIENCE
- 권
- 24
- 호
- 5
- 페이지
- 1 ~ 11+