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, Jingyu; Líu, Hao; Cao, Tianyu; Pang, Maogui; Guo, Meng; Wang, Xin; Zhao, Xiaodi; Lu, Yuanyuan

doi:10.1016/j.jbc.2022.102545

Cited by 4 publications

(5 citation statements)

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“…1H ). The results are inconsistent with published data [ 12 ]. Thus, an analysis of mRNA expression data from The Cancer Genome Atlas (TCGA) (dataset ID: TCGA.COADREAD.sampleMap/HiSeqV2) were performed to verify our results and revealed that the level of DKK4 expression was higher in cancer tissues than in normal tissues and was positively correlated with advanced diseases (Fig.…”

Section: Resultscontrasting

confidence: 99%

“…S1H‒J ). Our results are contradicting to the previous observations [ 12 ] and indicate that DKK4 acts as a key factor of poor prognosis of patients with colorectal cancers and promotes the CRC metastasis in mouse models. In our studies, CCSCs (3117, 3431, and 1597) derived from samples of three patients were used to address the role of DKK4 in CRC.…”

Section: Discussioncontrasting

confidence: 99%

“…Previous observation suggested that the survival time of CRC patients with high DKK4 expression was longer than that of patients with medium-low DKK4 expression [ 12 ]. However, we show here that DKK4 expression levels are negatively correlated with patient prognosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…DKK4 is downregulated in hepatocellular carcinoma [ 5 ] and is upregulated in many other cancers, including ovarian cancer [ 6 ], renal cell carcinoma [ 7 ], gastric cancer [ 8 ], and colorectal cancer (CRC) [ 9 ]. DKK4 might be involved in the invasion of epithelial ovarian cancer [ 6 ], inhibits the invasion of hepatocellular carcinoma [ 10 ] and colorectal carcinoma, and suppresses colorectal cancer metastasis [ 11 , 12 ]. DKK4 inhibition enhances chemosensitivity to current treatments in CRC [ 13 ] and non-small cell lung cancer [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

Li,

Chen,

et al. 2024

Oncogene

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Wnt/β-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased β-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/β-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/β-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of β-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/β-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates β-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced β-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced β-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

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Section: Resultscontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

Li,

Chen,

et al. 2024

Oncogene

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“…It has recently been found that DKK2 can also activate the WNT signaling pathway [ 8 , 9 ]. In contrast, DKK4 has mainly been associated with a large number of H. sapiens cancers, including colorectal cancer [ 10 ], melanomas [ 11 ], hepatocellular carcinomas [ 12 ], and gastric cancer [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Whole-Genome Identification and Characterization of the DKK Gene Family and Its Transcription Profiles: An Analysis of the Chinese Soft-Shell Turtle (Pelodiscus sinensis)

Wang,

Zhu,

Chen

et al. 2024

Animals

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The DKK family is a canonical small family of WNT antagonists. Though recent studies have suggested that the DKK gene family may be involved in sex differentiation in Pelodiscus sinensis, there are still a lot of things about the DKK gene family that we do not know. In this study, we used bioinformatics methods to identify members of the DKK gene family in P. sinensis and analyzed their phylogeny, covariance, gene structure, structural domains, promoter conserved sites, signal peptides, gonadal transcription factors, transcriptional profiles, and tissue expression profiles. Additionally, qRT-PCR results were utilized for the validation and preliminary investigation of the function of the DKK gene family in P. sinensis. The results showed that the DKK gene family is divided into six subfamilies, distributed on six different chromosomal scaffolds containing different gene structures and conserved motifs with the same structural domains, and all of the members were secreted proteins. Our transcriptional profiling and embryonic expression analysis showed that DKKL1 and DKK4 were significantly expressed in the testes, whereas DKK1 and DKK3 were significantly upregulated in the ovaries. This suggests a potential function in sex differentiation in P. sinensis. Our results may provide a basic theoretical basis for the sex differentiation process in P. sinensis.

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Grape Processing Waste: Effects on Inflammatory Bowel Disease and Colorectal Cancer

Laurindo

Direito

Otoboni

et al. 2023

Food Reviews International

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

Cited by 4 publications

References 30 publications

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

Whole-Genome Identification and Characterization of the DKK Gene Family and Its Transcription Profiles: An Analysis of the Chinese Soft-Shell Turtle (Pelodiscus sinensis)

Grape Processing Waste: Effects on Inflammatory Bowel Disease and Colorectal Cancer

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