Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.
Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.
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Dickkopf-2通过HNF 4 α1调节结直肠癌中的干细胞标志物LGR 5
DOI：
10.1016/j.isci.2021.102411
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发表时间：
2021-05-21
期刊：
影响因子：
5.8
通讯作者：
Bothwell ALM
中科院分区：
文献类型：
--
作者：
Shin JH;Jeong J;Choi J;Lim J;Dinesh RK;Braverman J;Hong JY;Maher SE;Amezcua Vesely MC;Kim W;Koo JH;Tang W;Wu D;Blackburn HN;Xicola RM;Llor X;Yilmaz O;Choi JM;Bothwell ALM
据报道，结直肠癌的干性增强有助于侵袭性进展，但其潜在机制仍不清楚。在这里，我们报告了Wnt配体，Dickkopf-2（DKK 2）是必不可少的发展结直肠癌干。在结肠炎相关癌症模型中，肠上皮细胞或干细胞中DKK 2的基因缺失减少了肿瘤发生和干细胞标记基因（包括LGR 5）的表达。结肠类器官中APC、KRAS、TP 53和SMAD 4基因的顺序突变揭示了APC敲除显著增加DKK 2表达，并通过额外的KRAS和TP 53突变进一步增加。此外，DKK 2激活原癌基因酪氨酸蛋白激酶Src，随后通过降解HNF 4 α1蛋白增加结直肠癌中表达LGR 5的细胞。这些发现表明，DKK 2是结肠上皮细胞在结肠直肠癌进展过程中增强LGR 5表达所必需的。APC、KRAS和TP 53突变诱导DKK 2在鼠结肠癌中的表达DKK 2增加结肠癌细胞中Src的磷酸化活化Src导致HNF 4 α1蛋白的降解此DKK 2下游信号传导增强结肠癌中LGR 5的表达细胞生物学;干细胞研究;癌症
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. APC, KRAS, and TP53 mutations induce DKK2 expression in murine colon cancer DKK2 increases Src phosphorylation in colon cancer cells Activated Src leads to degradation of HNF4α1 protein This DKK2 downstream signaling enhances LGR5 expression in colon cancer Cell Biology; Stem Cells Research; Cancer
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
胃Lgr5( )干细胞是小鼠侵袭性肠型胃癌的细胞起源。
影响因子：
44.1
作者：
Li, Xiu-Bin;Yang, Guan;Teng, Yan
通讯作者：
Teng, Yan
影响因子：
29.4
作者：
Gregorieff, A;Pinto, D;Clevers, H
通讯作者：
Clevers, H
影响因子：
5.3
作者：
Cattin, Anne-Laure;Le Beyec, Johanne;Ribeiro, Agnes
通讯作者：
Ribeiro, Agnes
影响因子：
14.8
作者：
Ran, F. Ann;Hsu, Patrick D.;Zhang, Feng
通讯作者：
Zhang, Feng