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,
WonJu 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
Affiliations
Jae Hun Shin
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
Jaekwang Jeong
Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Jungmin Choi
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea
Jaechul Lim
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
Ravi K. Dinesh
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
Jonathan Braverman
The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
Jun Young Hong
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
Stephen E. Maher
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
Maria C. Amezcua Vesely
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA
WonJu Kim
Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
Ja-Hyun Koo
Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
Wenwen Tang
Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
Dianqing Wu
Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
Holly N. Blackburn
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA; Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
Rosa M. Xicola
Department of Medicine and Cancer Center, Yale University, New Haven, CT 06520, USA
Xavier Llor
Department of Medicine and Cancer Center, Yale University, New Haven, CT 06520, USA
Omer Yilmaz
The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
Je-Min Choi
Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea
Alfred L.M. Bothwell
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA; Corresponding author
Summary: 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.
