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Wnt Signaling in Health and Diseases 2020
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Wnt Signaling in Health and Diseases 2020

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 33833

Special Issue Editor

Dr. Masaru Katoh

E-Mail Website1 Website2
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

Special Issue Information

Dear Colleagues,

WNT signals are transduced through Frizzled receptors and co-receptors to the canonical β-catenin-TCF/LEF signaling cascade and other non-canonical signaling cascades. WNT signaling cascades crosstalk 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 WNT signaling in cancers as well as con-cancerous diseases, with a strong emphasis on the improvement of knowledge for clinical application. Specific sub-topics covered may include but are not limited to the following:
(1) Studies using cutting-edge technologies, such as single-cell RNA sequencing, whole-genome sequencing, and the CRISPR-Cas9 gene-editing system, to demonstrate the involvement of WNT signaling cascades in human diseases;
(2) Studies using patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and cell line-derived xenografts (CDXs) to demonstrate the benefits of WNT-targeted therapeutics for cancerous and non-cancerous diseases;
(3) Studies using model animals, such as zebrafish, Xenopus, and engineered mice, to elucidate mechanisms of WNT-related pathologies.

Dr. Masaru Katoh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

Jump to: Review

20 pages, 6634 KiB  
Article
Integrative Analysis of Methylome and Transcriptome Reveals the Regulatory Mechanisms of Hair Follicle Morphogenesis in Cashmere Goat
by Shanhe Wang, Fang Li, Jinwang Liu, Yuelang Zhang, Yujie Zheng, Wei Ge, Lei Qu and Xin Wang
Cells 2020, 9(4), 969; https://doi.org/10.3390/cells9040969 - 14 Apr 2020
Cited by 26 | Viewed by 4989
Abstract
Studies in humans and mice have revealed that hair follicle morphogenesis relies on tightly coordinated ectodermal–mesodermal interactions, involving multiple signals and regulatory factors. DNA methylation and long non-coding RNA (lncRNA) play a critical role in early embryonic skin development by controlling gene expression. [...] Read more.
Studies in humans and mice have revealed that hair follicle morphogenesis relies on tightly coordinated ectodermal–mesodermal interactions, involving multiple signals and regulatory factors. DNA methylation and long non-coding RNA (lncRNA) play a critical role in early embryonic skin development by controlling gene expression. Acting as an indirect regulator, lncRNA could recruit DNA methyltransferases to specific genomic sites to methylate DNA. However, the molecular regulation mechanisms underlying hair follicle morphogenesis is unclear in cashmere goat. In this study, RNA-seq and whole-genome bisulfite sequencing (WGBS) in embryonic day 65 (E 65) and E 120 skin tissues of cashmere goat were used to reveal this complex regulatory process. The RNA-seq, qRT-PCR, and immunohistochemistry results showed that Wnt signaling played an important role in both hair follicle induction and differentiation stage; transcriptional factors (TFs), including HOXC13, SOX9, SOX21, JUNB, LHX2, VDR, and GATA3, participated in hair follicle differentiation via specific expression at E 120. Subsequently, the combination of WGBS and RNA-seq analysis showed that the expression of some hair follicle differentiation genes and TF genes were negatively correlated with the DNA methylation level generally. A portion of hair follicle differentiation genes were methylated and repressed in the hair follicle induction stage but were subsequently demethylated and expressed during the hair follicle differentiation stage, suggesting that DNA methylation plays an important role in hair morphogenesis by regulating associated gene expression. Furthermore, 45 upregulated and 147 downregulated lncRNAs in E 120 compared with E 65 were identified by lncRNA mapping, and then the potential differentially expressed lncRNAs associated with DNA methylation on the target gene were revealed. In conclusion, critical signals and genes were revealed during hair follicle morphogenesis in the cashmere goat. In this process, DNA methylation was lower in the hair follicle differentiation compared with the hair follicle induction stage and may play an important role in hair morphogenesis by regulating associated gene expression. Furthermore, potential lncRNAs associated with DNA methylation on target genes were delineated. This study enriches the regulatory network and molecular mechanisms on hair morphogenesis. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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18 pages, 8198 KiB  
Article
A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma
by Marianna Szemes, Zsombor Melegh, Jacob Bellamy, Alexander Greenhough, Madhu Kollareddy, Daniel Catchpoole and Karim Malik
Cells 2020, 9(3), 783; https://doi.org/10.3390/cells9030783 - 23 Mar 2020
Cited by 8 | Viewed by 6374
Abstract
The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We [...] Read more.
The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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15 pages, 3996 KiB  
Article
DKK1 Induced by 1,25D3 Is Required for the Mineralization of Osteoblasts
by Sungsin Jo, Subin Yoon, So Young Lee, So Yeon Kim, Hyosun Park, Jinil Han, Sung Hoon Choi, Joong-Soo Han, Jae-Hyuk Yang and Tae-Hwan Kim
Cells 2020, 9(1), 236; https://doi.org/10.3390/cells9010236 - 17 Jan 2020
Cited by 21 | Viewed by 4594
Abstract
1α,25-dihydroxyvitamin D3 (1,25D3), the most popular drug for osteoporosis treatment, drives osteoblast differentiation and bone mineralization. Wnt/β-catenin signaling is involved in commitment and differentiation of osteoblasts, but the role of the Dickkopf-related protein 1 (DKK1), a Wnt antagonist, in osteoblasts remains unknown. Here, [...] Read more.
1α,25-dihydroxyvitamin D3 (1,25D3), the most popular drug for osteoporosis treatment, drives osteoblast differentiation and bone mineralization. Wnt/β-catenin signaling is involved in commitment and differentiation of osteoblasts, but the role of the Dickkopf-related protein 1 (DKK1), a Wnt antagonist, in osteoblasts remains unknown. Here, we demonstrate the molecular mechanism of DKK1 induction by 1,25D3 and its physiological role during osteoblast differentiation. 1,25D3 markedly promoted the expression of both CCAAT/enhancer binding protein beta (C/EBPβ) and DKK1 at day 7 during osteoblast differentiation. Interestingly, mRNA and protein levels of C/EBPβ and DKK1 in osteoblasts were elevated by 1,25D3. We also found that C/EBPβ, in response to 1,25D3, directly binds to the human DKK1 promoter. Knockdown of C/EBPβ downregulated the expression of DKK1 in osteoblasts, which was partially reversed by 1,25D3. In contrast, overexpression of C/EBPβ upregulated DKK1 expression in osteoblasts, which was enhanced by 1,25D3. Furthermore, 1,25D3 treatment in osteoblasts stimulated secretion of DKK1 protein within the endoplasmic reticulum to extracellular. Intriguingly, blocking DKK1 attenuated calcified nodule formation in mineralized osteoblasts, but not ALP activity or collagen synthesis. Taken together, these observations suggest that 1,25D3 promotes the mineralization of osteoblasts through activation of DKK1 followed by an increase of C/EBPβ. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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Review

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31 pages, 2795 KiB  
Review
The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention
by Kerstin Menck, Saskia Heinrichs, Cornelia Baden and Annalen Bleckmann
Cells 2021, 10(1), 142; https://doi.org/10.3390/cells10010142 - 12 Jan 2021
Cited by 70 | Viewed by 9731
Abstract
The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can [...] Read more.
The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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20 pages, 3691 KiB  
Review
Wnt-5A/B Signaling in Hematopoiesis throughout Life
by Marina Mastelaro de Rezende, Giselle Zenker Justo, Edgar Julian Paredes-Gamero and Reinoud Gosens
Cells 2020, 9(8), 1801; https://doi.org/10.3390/cells9081801 - 29 Jul 2020
Cited by 10 | Viewed by 3529
Abstract
Wnt signaling is well-known to play major roles in the hematopoietic system, from embryogenesis to aging and disease. In addition to the main β-catenin-dependent pathway, it is now clear that Wnt5a and the structurally related Wnt5b are essential for hematopoiesis, bone marrow colonization [...] Read more.
Wnt signaling is well-known to play major roles in the hematopoietic system, from embryogenesis to aging and disease. In addition to the main β-catenin-dependent pathway, it is now clear that Wnt5a and the structurally related Wnt5b are essential for hematopoiesis, bone marrow colonization and the final steps of hematopoietic stem cell (HSC) maturation via β-catenin-independent signaling. Wnt5a and Wnt5b ligands prevent hematopoietic exhaustion (by maintaining quiescent, long-term HSCs), induce the proliferation of progenitors, and guide myeloid development, in addition to being involved in the development of aging-related alterations. The aim of this review is to summarize the current knowledge on these roles of Wnt5a and Wn5b signaling in the hematopoietic field. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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20 pages, 1177 KiB  
Review
The Significance of the Dysregulation of Canonical Wnt Signaling in Head and Neck Squamous Cell Carcinomas
by Jarosław Paluszczak
Cells 2020, 9(3), 723; https://doi.org/10.3390/cells9030723 - 15 Mar 2020
Cited by 25 | Viewed by 3892
Abstract
The knowledge about the molecular alterations which are found in head and neck squamous cell carcinomas (HNSCC) has much increased in recent years. However, we are still awaiting the translation of this knowledge to new diagnostic and therapeutic options. Among the many molecular [...] Read more.
The knowledge about the molecular alterations which are found in head and neck squamous cell carcinomas (HNSCC) has much increased in recent years. However, we are still awaiting the translation of this knowledge to new diagnostic and therapeutic options. Among the many molecular changes that are detected in head and neck cancer, the abnormalities in several signaling pathways, which regulate cell proliferation, cell death and stemness, seem to be especially promising with regard to the development of targeted therapies. Canonical Wnt signaling is a pathway engaged in the formation of head and neck tissues, however it is not active in adult somatic mucosal cells. The aim of this review paper is to bring together significant data related to the current knowledge on the mechanisms and functional significance of the dysregulation of the Wnt/β-catenin pathway in head and neck tumors. Research evidence related to the role of Wnt signaling activation in the stimulation of cell proliferation, migration and inhibition of apoptosis in HNSCC is presented. Moreover, its role in promoting stemness traits in head and neck cancer stem-like cells is described. Evidence corroborating the hypothesis that the Wnt signaling pathway is a very promising target of novel therapeutic interventions in HNSCC is also discussed. Full article
(This article belongs to the Special Issue Wnt Signaling in Health and Diseases 2020)
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