期刊
ONCOGENE
卷 40, 期 26, 页码 4486-4502出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-01860-z
关键词
-
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [16H06374, 16H06944, 18K15064, 20K16330, 20K07311]
- Japan Agency for Medical Research and development, AMED [18cm0106132h0001, 20cm0106152h0002]
- Yasuda Memorial Foundation
- Ichiro Kanehara Foundation of the Promotion of Medical Science Medical Care
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University
- Grants-in-Aid for Scientific Research [20K16330, 20K07311, 16H06944, 16H06374, 18K15064] Funding Source: KAKEN
Dickkopf1 (DKK1) is overexpressed in cancer, promoting cell proliferation by interacting with cytoskeleton-associated protein 4 (CKAP4). The transcription factor forkhead box M1 (FOXM1) and its target genes show coordinated expression with DKK1, forming a positive feedback loop to enhance cancer cell proliferation. This interaction is independent of the Wnt signaling pathway and is associated with poorer prognosis in pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC) patients.
Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5MODIFIER LETTER PRIME-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据