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Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway

Aberrant activation of the Wnt/β-catenin signaling pathway is implicated in most malignant cancers, especially in the initiation and progression of colorectal cancer (CRC). DKK4 is a classical inhibitory molecule of the Wnt/β-catenin pathway, but its role in CRC is ambiguous, and the molecular mecha...

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Autores principales: Liang, Junrong, Sun, Lina, Li, Yujun, Liu, Wanning, Li, Danxiu, Chen, Ping, Wang, Xin, Hui, Juan, Zhou, Jinchi, Liu, Hao, Cao, Tianyu, Pang, Maogui, Guo, Meng, Zhao, Xiaodi, Lu, Yuanyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640985/
https://www.ncbi.nlm.nih.gov/pubmed/36181792
http://dx.doi.org/10.1016/j.jbc.2022.102545
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author Liang, Junrong
Sun, Lina
Li, Yujun
Liu, Wanning
Li, Danxiu
Chen, Ping
Wang, Xin
Hui, Juan
Zhou, Jinchi
Liu, Hao
Cao, Tianyu
Pang, Maogui
Guo, Meng
Wang, Xin
Zhao, Xiaodi
Lu, Yuanyuan
author_facet Liang, Junrong
Sun, Lina
Li, Yujun
Liu, Wanning
Li, Danxiu
Chen, Ping
Wang, Xin
Hui, Juan
Zhou, Jinchi
Liu, Hao
Cao, Tianyu
Pang, Maogui
Guo, Meng
Wang, Xin
Zhao, Xiaodi
Lu, Yuanyuan
author_sort Liang, Junrong
collection PubMed
description Aberrant activation of the Wnt/β-catenin signaling pathway is implicated in most malignant cancers, especially in the initiation and progression of colorectal cancer (CRC). DKK4 is a classical inhibitory molecule of the Wnt/β-catenin pathway, but its role in CRC is ambiguous, and the molecular mechanism remains unclear. Here, we determined DKK4 expression was significantly upregulated in 23 CRC cell lines and 229 CRC tissues when analyzed by quantitative PCR and immunohistochemistry, respectively. Our analysis of tissue samples indicated the survival time of CRC patients with high DKK4 expression was longer than that of patients with medium-low DKK4 expression. We examined the effects of DKK4 on cell proliferation and metastasis by cell counting kit-8 assays, transwell assays, and subcutaneous and metastatic mouse tumor models, and we discovered that DKK4 silencing promoted the metastasis of CRC cells both in vitro and in vivo. Our RNA-seq analysis revealed that AKT2, FZD6, and JUN, which play important roles in AKT and Wnt signaling, were significantly increased after DKK4 knockdown. DKK4 represses Wnt/β-catenin signaling by repressing FZD6 and AKT2/s552 β-catenin in CRC. Further experiments revealed recombinant Wnt3a and LiCl could induce DKK4 expression. Moreover, our bioinformatics analysis and luciferase reporter assays identified posttranscriptional regulators of DKK4 in CRC cells. In summary, DKK4 is elevated in CRC and inhibits cell metastasis by a novel negative feedback mechanism of the Wnt3a/DKK4/AKT/s552 β-catenin regulatory axis to restrict overactivation of Wnt activity in CRC. Therefore, DKK4 restoration may be applied as a potential CRC therapeutic strategy.
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spelling pubmed-96409852022-11-14 Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway Liang, Junrong Sun, Lina Li, Yujun Liu, Wanning Li, Danxiu Chen, Ping Wang, Xin Hui, Juan Zhou, Jinchi Liu, Hao Cao, Tianyu Pang, Maogui Guo, Meng Wang, Xin Zhao, Xiaodi Lu, Yuanyuan J Biol Chem Research Article Aberrant activation of the Wnt/β-catenin signaling pathway is implicated in most malignant cancers, especially in the initiation and progression of colorectal cancer (CRC). DKK4 is a classical inhibitory molecule of the Wnt/β-catenin pathway, but its role in CRC is ambiguous, and the molecular mechanism remains unclear. Here, we determined DKK4 expression was significantly upregulated in 23 CRC cell lines and 229 CRC tissues when analyzed by quantitative PCR and immunohistochemistry, respectively. Our analysis of tissue samples indicated the survival time of CRC patients with high DKK4 expression was longer than that of patients with medium-low DKK4 expression. We examined the effects of DKK4 on cell proliferation and metastasis by cell counting kit-8 assays, transwell assays, and subcutaneous and metastatic mouse tumor models, and we discovered that DKK4 silencing promoted the metastasis of CRC cells both in vitro and in vivo. Our RNA-seq analysis revealed that AKT2, FZD6, and JUN, which play important roles in AKT and Wnt signaling, were significantly increased after DKK4 knockdown. DKK4 represses Wnt/β-catenin signaling by repressing FZD6 and AKT2/s552 β-catenin in CRC. Further experiments revealed recombinant Wnt3a and LiCl could induce DKK4 expression. Moreover, our bioinformatics analysis and luciferase reporter assays identified posttranscriptional regulators of DKK4 in CRC cells. In summary, DKK4 is elevated in CRC and inhibits cell metastasis by a novel negative feedback mechanism of the Wnt3a/DKK4/AKT/s552 β-catenin regulatory axis to restrict overactivation of Wnt activity in CRC. Therefore, DKK4 restoration may be applied as a potential CRC therapeutic strategy. American Society for Biochemistry and Molecular Biology 2022-09-29 /pmc/articles/PMC9640985/ /pubmed/36181792 http://dx.doi.org/10.1016/j.jbc.2022.102545 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Liang, Junrong
Sun, Lina
Li, Yujun
Liu, Wanning
Li, Danxiu
Chen, Ping
Wang, Xin
Hui, Juan
Zhou, Jinchi
Liu, Hao
Cao, Tianyu
Pang, Maogui
Guo, Meng
Wang, Xin
Zhao, Xiaodi
Lu, Yuanyuan
Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title_full Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title_fullStr Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title_full_unstemmed Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title_short Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway
title_sort wnt signaling modulator dkk4 inhibits colorectal cancer metastasis through an akt/wnt/β-catenin negative feedback pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640985/
https://www.ncbi.nlm.nih.gov/pubmed/36181792
http://dx.doi.org/10.1016/j.jbc.2022.102545
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