Oncogenic Function of DACT1 in Colon Cancer through the Regulation of β-catenin

Yuan, Gang; Wang, Chongkai; Ma, Caihong; Chen, Ning; Tian, Qinghe; Zhang, Tonglin; Fu, Wei

doi:10.1371/journal.pone.0034004

Cited by 35 publications

(31 citation statements)

References 45 publications

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“…However, most of these studies described strong activation of the Wnt/β-catenin pathway in colon cancer cell lines, resulting from gain-of-function mutations in β-catenin (HCT116, SW48, Colo205, LS174T) or loss-of-function mutations in the destruction complex component APC (SW480, HT29, DLD1, LoVo, SW620, Caco2, Colo205, SW1116, Colo320) [36, 37]. Increasing evidence has confirmed that these tumor-causative mutations lead to defective stabilization of β-catenin and loss of nuclear β-catenin/TCF-dependent translocation, and further activate downstream target genes related to cell proliferation and transformation [38].…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Wang

Yue

Shao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aberrant activation of the Wnt/β-catenin signaling pathway plays a key role in the pathogenesis of multiple tumors including digestive cancers. Recent studies have reported that Dickkopf-related protein 2 (DKK2) is epigenetically inactivated in numerous types of cancers and that its gene products exhibit tumor-suppressive properties. However, the biological functions and underlying molecular mechanisms of DKK2 in colon carcinoma remains obscure. Methods: We examined the expression of DKK2 in colon tumor cell lines by RT-PCR and its promoter methylation status in colon tumor cell lines and primary tumors by methylation-specific PCR (MSP). Ectopic expression of DKK2 was measured by RT-PCR prior to the other experiments. To investigate the function of DKK2, we assayed colony formation and cell proliferation, utilized flow cytometric analyses of the cell cycle and acridine orange/ethidium bromide (AO/EB) fluorescence staining for apoptosis, and examined wound healing, transwell migration and tumor growth in vivo. Western blots were used to explore the mechanisms of DKK2 in epithelial- mesenchymal transition and canonical Wnt/β-catenin signaling. Results: We show here that downregulation or silencing of DKK2 was closely associated with the hypermethylation status of its promoter and that DKK2 expression could be restored by demethylation treatment. Methylation of the DKK2 promoter was detected in nearly all tumors and tumor-adjacent tissues, but not in normal colon tissues. Ectopic expression of DKK2 in colon cell lines HCT116 and HT-29 inhibited colony formation and cell viability by inducing cell cycle G0/G1 arrest and apoptosis, and growth of stable DKK2-infected HCT116 cells in nude mice was decreased compared to controls. Furthermore, DKK2 restrained cell migration through partial reversal of epithelial-to- mesenchymal transition and also by downregulating several stem cell markers. Our data further showed that restoration of DKK2 expression resulted in downregulation of active β-catenin and its downstream target genes. Conclusion: DKK2 appears to be a functional tumor suppressor regulating tumorigenesis of colorectal cancer by antagonizing Wnt/β-catenin signaling.

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Section: Discussionmentioning

confidence: 99%

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Wang

Yue

Shao

et al. 2017

Cell Physiol Biochem

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“…Previous evidence indicates that inflammation has an important role in the development of asthma, and various cytokines secreted by inflammatory cells regulate airway hyperresponsiveness and remodeling (27,28 (15) demonstrated that DACT1 was a positive regulator of β-catenin; however, the correlation of DACT1 and β-catenin in asthma remains unclear. The present results indicated that upregulation of DACT1 expression could inhibit the expression and nuclear translocation of β-catenin in macrophage cell line, RAW264.7, as well as upregulate the expression of IL13, IL5 and IL6 mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…As a tumor suppressor, DACT1 is downregulated in multiple tumor types, such as liver, colon and breast cancer (12). It has been demonstrated that DACT1 functions in the development of tumors primarily by regulating signaling pathways, such as Wnt and the c-Jun N-terminal kinase pathway (13)(14)(15). For instance, DACT1 binds to disheveled homolog 1 (Dvl1) to induce the degradation of Dvl1 and the subsequent inhibition of the Wnt/β-catenin pathway (16).…”

Section: Introductionmentioning

confidence: 99%

Expression of DACT1 in children with asthma and its regulation mechanism

et al. 2018

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Abstract. The aim of the present study was to detect DACT1 expression levels in the lungs of children with asthma, and to investigate its role and molecular mechanisms in regulating the expression of inflammatory factors in RAW264.7 cells. DACT1, DACT2 and DACT3 expression was analyzed in biopsy specimens from 10 cases of newly diagnosed children with asthma and 10 healthy controls by reverse transcription-quantitative polymerase chain reaction, and their expression was confirmed in RAW264.7 cells. DACT1 expression was silenced by small interfering RNA or enhanced by transfection of pcDNA-3.1-DACT1 in RAW264.7 cells, and expression of β-catenin and inflammatory factors, interleukin (IL) 5, IL6 and IL13, was analyzed. Nuclear translocation of β-catenin was detected by western blot analysis, and the effect of DACT1 on β-catenin was investigated with rescue experiments. Regulation of the Wnt signaling pathway by DACT1 and β-catenin was analyzed in RAW264.7 cells after recombinant Wnt5A stimulation. DACT1, DACT2 and DACT3 were significantly upregulated in specimens from children with asthma compared with controls (P<0.05) and the expression of DACT1 was significantly more increased compared with DACT2 and DACT3 (P<0.05). Inhibition of DACT1 expression significantly suppressed IL5, IL6 and IL13 mRNA expression levels compared with the control (P<0.05), while upregulated DACT1 expression significantly increased IL5, IL6 and IL13 mRNA expression (P<0.05). DACT1 inhibited the expression and nuclear translocation of β-catenin, while overexpression of β-catenin significantly inhibited the biological function of DACT1 (P<0.05). Overexpression of β-catenin also significantly suppressed the upregulation of IL5, IL6 and IL13 mRNA induced by pcDNA3.1-DACT1 transfection (P<0.05). Following the addition of Wnt5A, overexpression of DACT1 inhibited the expression and nuclear translocation of β-catenin, and upregulated IL5, IL6 and IL13 mRNA expression. In conclusion, DACT1 was indicated to be upregulated in lung tissues from children with asthma, which could induce higher pro-inflammatory factor expression. DACT1 may act via inhibiting the expression and nuclear translocation of β-catenin, a factor in the Wnt signaling pathway. The present results suggested that DACT1 may be a potential target for the treatment of asthma.

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“…But in a recent development (Yuan et al 18 ) it has been found that expression of DACT 1 positively regulates β-catenin. Both scenarios need to be checked via inspection of the estimated probability values for β-catenin using the test data.…”

Section: Hold Out Exprimentmentioning

confidence: 99%

“…Concentration of β-catenin given concentrations of DV L2 and DACT 1 varies and for static model it is tough to assign probability values. High DV L2 concentration or suppression (expression) of DACT 1 leads to increase in concentration of β-catenin ( 3 , Yuan et al 18 ). Wet lab experimental evaluations might reveal the factual proportions.…”

Section: Assumed and Estimated Probabilities From Literaturementioning

confidence: 99%

A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in Matlab

Sinha¹

2014

Preprint

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A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in Matlab ‡ Shriprakash Sinha * a Insight, Innovation and Integration Simulation study involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition who intend to work on modeling of the pathway. This paucity might happen due to restrictive policies which enforce an unwanted embargo on the sharing of important scientific knowledge. The manuscript elucidates embedding of prior biological knowledge, integration of heterogeneous information, transformation of biological hypothesis into computational framework and design of experiments in a simple manner interleaved with aspects of Bayesian Network toolbox and Matlab code so as to help readers get a feel of a project related to modeling of the pathway. Abstract A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid bio-logists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian Network toolbox. This is done in order to ease the understanding of beginner students and researchers in transition to computational signaling biology, who intend to work in the field of modeling of signaling pathways. The manuscript expounds the computational flow of the contents in advance article 1 via code development and takes the reader in a step by step process of how • the collection and the transformation of the available biological information from literature is done, • the integration of the heterogeneous data and prior biological knowledge in the network is achieved, • conditional probability tables for nodes in biologically inspired tables are estimated, • the simulation study is designed, • the hypothesis regarding a biological phenomena is transformed into computational framework, and • results and inferences drawn using d-connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands on experience of a perturbation project. Matlab code with dataset is made available under GNU GPL v3 license at google code project on https://code.google.com/p/ static-bn-for-wnt-signaling-pathway ‡ This manuscript is a part of the Netherlands Bioinformatics Centre (NBIC) BioRange-II project BR2.5 (code-IGD71G). It complements and uses material from Sinha

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Oncogenic Function of DACT1 in Colon Cancer through the Regulation of β-catenin

Cited by 35 publications

References 45 publications

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Expression of DACT1 in children with asthma and its regulation mechanism

A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in Matlab

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