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Wnt Signaling in Health and Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 95439

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Dr. Masaru Katoh

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Guest Editor

National Cancer Center, Tokyo, Japan
Interests: precision medicine; human genetics; FGF signaling; Hedgehog signaling; WNT signaling; tumor microenvironment; angiogenesis; immuno-oncology
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

WNT signals are transduced through frizzled receptors and co-receptors to the WNT/β-catenin, WNT/stabilization of proteins (STOP), WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR), and WNT/receptor tyrosine kinase (RTK) signaling cascades. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog, and TGFβ/BMP signaling cascades to regulate embryogenesis, tissue homeostasis, and tumorigenesis.

Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome, and PCP-related diseases. By contrast, somatic alterations in WNT signaling components, such as APC, AXIN2, CTNNB1, RSPO2, RSPO3, and RNF43, occur in colorectal cancer and other types of human cancers.

This Special Issue is calling for reviews and original articles covering translational research on the WNT signaling in cancers as well as con-cancerous diseases, with strong emphasis on the improvement of knowledge for clinical application.

Dr. Masaru Katoh
Guest Editor

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Keywords

WNT signaling
Frizzled
β-catenin
stem cells
planar cell polarity
colorectal cancer
breast cancer
gastric cancer
lung cancer
sarcomas
immune evasion

Published Papers (13 papers)

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Research

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14 pages, 1996 KiB

Open AccessArticle

Plant MIR167e-5p Inhibits Enterocyte Proliferation by Targeting β-Catenin

by Meng Li, Ting Chen, Jia-Jian He, Jia-Han Wu, Jun-Yi Luo, Rui-Song Ye, Mei-Ying Xie, Hao-Jie Zhang, Bin Zeng, Jie Liu, Qian-Yun Xi, Qing-Yan Jiang, Jia-Jie Sun and Yong-Liang Zhang

Cells 2019, 8(11), 1385; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111385 - 04 Nov 2019

Cited by 30 | Viewed by 3677

Abstract

MicroRNAs (miRNAs) are important negative regulators of genes involved in physiological and pathological processes in plants and animals. It is worth exploring whether plant miRNAs play a cross-kingdom regulatory role in animals. Herein, we found that plant MIR167e-5p regulates the proliferation of enterocytes in vitro. A porcine jejunum epithelial cell line (IPEC-J2) and a human colon carcinoma cell line (Caco-2) were treated with 0, 10, 20, and 40 pmol of synthetic 2′-O-methylated plant MIR167e-5p, followed by a treatment with 20 pmol of MIR167e-5p for 0, 24, 48, and 72 h. The cells were counted, and IPEC-J2 cell viability was determined by the MTT and EdU assays at different time points. The results showed that MIR167e-5p significantly inhibited the proliferation of enterocytes in a dose- and time-dependent manner. Bioinformatics prediction and a luciferase reporter assay indicated that MIR167e-5p targets β-catenin. In IPEC-J2 and Caco-2 cells, MIR167e-5p suppressed proliferation by downregulating β-catenin mRNA and protein levels. MIR167e-5p relieved this inhibition. Similar results were achieved for the β-catenin downstream target gene c-Myc and the proliferation-associated gene PCNA. This research demonstrates that plant MIR167e-5p can inhibit enterocyte proliferation by targeting the β-catenin pathway. More importantly, plant miRNAs may be a new class of bioactive molecules for epigenetic regulation in humans and animals. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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16 pages, 4336 KiB

Open AccessArticle

Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors

by Xinhui Wu, Eline M. van Dijk, John-Poul Ng-Blichfeldt, I. Sophie T. Bos, Chiara Ciminieri, Melanie Königshoff, Loes E.M. Kistemaker and Reinoud Gosens

Cells 2019, 8(10), 1147; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101147 - 25 Sep 2019

Cited by 35 | Viewed by 5125

Abstract

Chronic obstructive pulmonary disease (COPD) represents a worldwide concern with high morbidity and mortality, and is believed to be associated with accelerated ageing of the lung. Alveolar abnormalities leading to emphysema are a key characteristic of COPD. Pulmonary alveolar epithelial type 2 cells (AT2) produce surfactant and function as progenitors for type 1 cells. Increasing evidence shows elevated WNT-5A/B expression in ageing and in COPD that may contribute to the disease process. However, supportive roles for WNT-5A/B in lung regeneration were also reported in different studies. Thus, we explored the role of WNT-5A/B on alveolar epithelial progenitors (AEPs) in more detail. We established a Precision-Cut-Lung Slices (PCLS) model and a lung organoid model by co-culturing epithelial cells (EpCAM⁺/CD45^-/CD31^-) with fibroblasts in matrigel in vitro to study the impact of WNT-5A and WNT-5B. Our results show that WNT-5A and WNT-5B repress the growth of epithelial progenitors with WNT-5B preferentially restraining the growth and differentiation of alveolar epithelial progenitors. We provide evidence that both WNT-5A and WNT-5B negatively regulate the canonical WNT signaling pathway in alveolar epithelium. Taken together, these findings reveal the functional impact of WNT-5A/5B signaling on alveolar epithelial progenitors in the lung, which may contribute to defective alveolar repair in COPD. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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22 pages, 4721 KiB

Open AccessArticle

An Autocrine Wnt5a Loop Promotes NF-κB Pathway Activation and Cytokine/Chemokine Secretion in Melanoma

by Gastón Barbero, María Victoria Castro, María Belén Villanueva, María Josefina Quezada, Natalia Brenda Fernández, Sharon DeMorrow and Pablo Lopez-Bergami

Cells 2019, 8(9), 1060; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091060 - 10 Sep 2019

Cited by 30 | Viewed by 4704

Abstract

Wnt5a signaling has been implicated in the progression of cancer by regulating multiple cellular processes, largely migration and invasion, epithelial-mesenchymal transition (EMT), and metastasis. Since Wnt5a signaling has also been involved in inflammatory processes in infectious and inflammatory diseases, we addressed the role of Wnt5a in regulating NF-κB, a pivotal mediator of inflammatory responses, in the context of cancer. The treatment of melanoma cells with Wnt5a induced phosphorylation of the NF-κB subunit p65 as well as IKK phosphorylation and IκB degradation. By using cDNA overexpression, RNA interference, and dominant negative mutants we determined that ROR1, Dvl2, and Akt (from the Wnt5a pathway) and TRAF2 and RIP (from the NF-κB pathway) are required for the Wnt5a/NF-κB crosstalk. Wnt5a also induced p65 nuclear translocation and increased NF-κB activity as evidenced by reporter assays and a NF-κB-specific upregulation of RelB, Bcl-2, and Cyclin D1. Further, stimulation of melanoma cells with Wnt5a increased the secretion of cytokines and chemokines, including IL-6, IL-8, IL-11, and IL-6 soluble receptor, MCP-1, and TNF soluble receptor I. The inhibition of endogenous Wnt5a demonstrated that an autocrine Wnt5a loop is a major regulator of the NF-κB pathway in melanoma. Taken together, these results indicate that Wnt5a activates the NF-κB pathway and has an immunomodulatory effect on melanoma through the secretion of cytokines and chemokines. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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13 pages, 2238 KiB

Open AccessArticle

Wnt10b Participates in Regulating Fatty Acid Synthesis in the Muscle of Zebrafish

by Dongwu Liu, Qiuxiang Pang, Qiang Han, Qilong Shi, Qin Zhang and Hairui Yu

Cells 2019, 8(9), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091011 - 30 Aug 2019

Cited by 11 | Viewed by 3422

Abstract

There are 19 Wnt genes in mammals that belong to 12 subfamilies. Wnt signaling pathways participate in regulating numerous homeostatic and developmental processes in animals. However, the function of Wnt10b in fatty acid synthesis remains unclear in fish species. In the present study, we uncovered the role of the Wnt10b signaling pathway in the regulation of fatty acid synthesis in the muscle of zebrafish. The gene of Wnt10b was overexpressed in the muscle of zebrafish using pEGFP-N1-Wnt10b vector injection, which significantly decreased the expression of glycogen synthase kinase 3β (GSK-3β), but increased the expression of β-catenin, peroxisome proliferators-activated receptor γ (PPARγ), and CCAAT/enhancer binding protein α (C/EBPα). Moreover, the activity and mRNA expression of key lipogenic enzymes ATP-citrate lyase (ACL), acetyl-CoA carboxylase (ACC) and fatty acid synthetase (FAS), and the content of non-esterified fatty acids (NEFA), total cholesterol (TC), and triglyceride (TG) were also significantly decreased. Furthermore, interference of the Wnt10b gene significantly inhibited the expression of β-catenin, PPARγ, and C/EBPα, but significantly induced the expression of GSK-3β, FAS, ACC, and ACL. The content of NEFA, TC, and TG as well as the activity of FAS, ACC, and ACL significantly increased. Thus, our results showed that Wnt10b participates in regulating fatty acid synthesis via β-catenin, C/EBPα and PPARγ in the muscle of zebrafish. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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22 pages, 11997 KiB

Open AccessArticle

Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling

by Dattatrya Shetti, Bao Zhang, Conghui Fan, Canlong Mo, Bae Hoon Lee and Kun Wei

Cells 2019, 8(8), 892; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080892 - 14 Aug 2019

Cited by 58 | Viewed by 7290

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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Review

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18 pages, 1224 KiB

Open AccessReview

Wnt Signalling in Acute Myeloid Leukaemia

by Alicja M. Gruszka, Debora Valli and Myriam Alcalay

Cells 2019, 8(11), 1403; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111403 - 07 Nov 2019

Cited by 54 | Viewed by 6812

Abstract

Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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21 pages, 1367 KiB

Open AccessReview

Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects

by Mingqin Wang, Patrizia de Marco, Valeria Capra and Zoha Kibar

Cells 2019, 8(10), 1198; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101198 - 04 Oct 2019

Cited by 51 | Viewed by 9398

Abstract

Neural tube defects (NTDs), including spina bifida and anencephaly, represent the most severe and common malformations of the central nervous system affecting 0.7–3 per 1000 live births. They result from the failure of neural tube closure during the first few weeks of pregnancy. They have a complex etiology that implicate a large number of genetic and environmental factors that remain largely undetermined. Extensive studies in vertebrate models have strongly implicated the non-canonical Wnt/planar cell polarity (PCP) signaling pathway in the pathogenesis of NTDs. The defects in this pathway lead to a defective convergent extension that is a major morphogenetic process essential for neural tube elongation and subsequent closure. A large number of genetic studies in human NTDs have demonstrated an important role of PCP signaling in their etiology. However, the relative contribution of this pathway to this complex etiology awaits a better picture of the complete genetic architecture of these defects. The emergence of new genome technologies and bioinformatics pipelines, complemented with the powerful tool of animal models for variant interpretation as well as significant collaborative efforts, will help to dissect the complex genetics of NTDs. The ultimate goal is to develop better preventive and counseling strategies for families affected by these devastating conditions. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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40 pages, 2535 KiB

Open AccessReview

Wnt Signaling in Neural Crest Ontogenesis and Oncogenesis

by Yu Ji, Hongyan Hao, Kurt Reynolds, Moira McMahon and Chengji J. Zhou

Cells 2019, 8(10), 1173; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101173 - 29 Sep 2019

Cited by 37 | Viewed by 13277

Abstract

Neural crest (NC) cells are a temporary population of multipotent stem cells that generate a diverse array of cell types, including craniofacial bone and cartilage, smooth muscle cells, melanocytes, and peripheral neurons and glia during embryonic development. Defective neural crest development can cause severe and common structural birth defects, such as craniofacial anomalies and congenital heart disease. In the early vertebrate embryos, NC cells emerge from the dorsal edge of the neural tube during neurulation and then migrate extensively throughout the anterior-posterior body axis to generate numerous derivatives. Wnt signaling plays essential roles in embryonic development and cancer. This review summarizes current understanding of Wnt signaling in NC cell induction, delamination, migration, multipotency, and fate determination, as well as in NC-derived cancers. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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20 pages, 2318 KiB

Open AccessReview

Intracellular Signals Activated by Canonical Wnt Ligands Independent of GSK3 Inhibition and β-Catenin Stabilization

by Antonio García de Herreros and Mireia Duñach

Cells 2019, 8(10), 1148; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101148 - 25 Sep 2019

Cited by 33 | Viewed by 6098

Abstract

In contrast to non-canonical ligands, canonical Wnts promote the stabilization of β-catenin, which is a prerequisite for formation of the TCF4/β-catenin transcriptional complex and activation of its target genes. This pathway is initiated by binding of Wnt ligands to the Frizzled/LRP5/6 receptor complex, and it increases the half-life of β-catenin by precluding the phosphorylation of β-catenin by GSK3 and its binding to the βTrCP1 ubiquitin ligase. Other intercellular signals are also activated by Wnt ligands that do not inhibit GSK3 and increase β-catenin protein but that either facilitate β-catenin transcriptional activity or stimulate other transcriptional factors that cooperate with it. In this review, we describe the layers of complexity of these signals and discuss their crosstalk with β-catenin in activation of transcriptional targets. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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32 pages, 1914 KiB

Open AccessEditor’s ChoiceReview

WNT Signaling in Disease

by Li Fang Ng, Prameet Kaur, Nawat Bunnag, Jahnavi Suresh, Isabelle Chiao Han Sung, Qian Hui Tan, Jan Gruber and Nicholas S. Tolwinski

Cells 2019, 8(8), 826; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080826 - 03 Aug 2019

Cited by 151 | Viewed by 16077

Abstract

Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. Here, [...] Read more.

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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12 pages, 1051 KiB

Open AccessReview

Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

by Hanna Karvonen, Harlan Barker, Laura Kaleva, Wilhelmiina Niininen and Daniela Ungureanu

Cells 2019, 8(8), 812; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080812 - 02 Aug 2019

Cited by 29 | Viewed by 7132

Abstract

Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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26 pages, 4055 KiB

Open AccessEditor’s ChoiceReview

Targeting the Canonical WNT/β-Catenin Pathway in Cancer Treatment Using Non-Steroidal Anti-Inflammatory Drugs

by Alexandre Vallée, Yves Lecarpentier and Jean-Noël Vallée

Cells 2019, 8(7), 726; https://doi.org/10.3390/cells8070726 - 15 Jul 2019

Cited by 66 | Viewed by 8747

Abstract

Chronic inflammation and oxidative stress are common and co-substantial pathological processes accompanying and contributing to cancers. Numerous epidemiological studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) could have a positive effect on both the prevention of cancer and tumor therapy. Numerous hypotheses have postulated that NSAIDs could slow tumor growth by acting on both chronic inflammation and oxidative stress. This review takes a closer look at these hypotheses. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. This pathway is closely associated with both chronic inflammation and oxidative stress in cancers. The administration of NSAIDs has been observed to help in the downregulation of the WNT/β-catenin pathway and thus in the control of tumor growth. NSAIDs act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in opposing manners. PPARγ agonists can promote cell cycle arrest, cell differentiation, and apoptosis, and can reduce inflammation, oxidative stress, proliferation, invasion, and cell migration. In parallel, the dysregulation of circadian rhythms (CRs) contributes to cancer development through the upregulation of the canonical WNT/β-catenin pathway. By stimulating PPARγ expression, NSAIDs can control CRs through the regulation of many key circadian genes. The administration of NSAIDs in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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Other

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12 pages, 3629 KiB

Open AccessBrief Report

Wnt Receptor Frizzled-4 as a Marker for Isolation of Enteric Neural Progenitors in Human Children

by Peter H. Neckel, Melanie Scharr, Karin Seid, Katharina Nothelfer, Jörg Fuchs, Florian Obermayr, Bernhard Hirt, Stephan M. Huber and Lothar Just

Cells 2019, 8(8), 792; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080792 - 30 Jul 2019

Cited by 1 | Viewed by 2967

Abstract

Identification and isolation of neural progenitor cells from the human enteric nervous system (ENS) is currently hampered by the lack of reliable, specific markers. Here, we define the Wnt-receptor frizzled-4 as a marker for the isolation of enteric neural progenitor cells derived from paediatric gut samples. We show that the Wnt-receptor frizzled-4 is expressed in the human colon and in Tunica muscularis-derived enterospheres. To obtain a purified culture, we carried out fluorescence-activated cell sorting (FACS) using PE-conjugated frizzled-4 antibodies. Frizzled-4^positive cells gave rise to neurosphere-like bodies and ultimately differentiated into neurons as revealed by BrdU-proliferation assays and immunocytochemistry, whereas in frizzled-4^negative cultures we did not detect any neuronal and glial cells. By using a patch-clamp approach, we also demonstrated the expression of functional sodium and potassium channels in frizzled-4^positive cell cultures after differentiation in vitro. Full article

(This article belongs to the Special Issue Wnt Signaling in Health and Diseases)

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