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
Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA.
Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
iScience. 2021 Apr 15;24(5):102411. doi: 10.1016/j.isci.2021.102411. eCollection 2021 May 21.
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 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including in a model of colitis-associated cancer. Sequential mutations in , , , and genes in colonic organoids revealed a significant increase of expression by APC knockout and further increased by additional and 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.
已有报道称结直肠癌中的干性增强，这有助于肿瘤的侵袭性进展，但其潜在机制仍不清楚。在此，我们报告一种Wnt配体Dickkopf-2（DKK2）对于结直肠癌干性的发展至关重要。在肠道上皮细胞或干细胞中基因敲除DKK2可减少在结肠炎相关癌模型中的肿瘤发生以及包括[具体基因]在内的干细胞标记基因的表达。结肠类器官中[相关基因]的序列突变显示，APC基因敲除后DKK2表达显著增加，而额外的[其他基因]和[其他基因]突变进一步增加了DKK2的表达。此外，DKK2通过降解HNF4α1蛋白激活原癌基因酪氨酸蛋白激酶Src，随后结直肠癌中LGR5表达细胞增加。这些发现表明，在结直肠癌进展过程中，结肠上皮细胞增强LGR5表达需要DKK2。
