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24 pages, 1451 KiB

Open AccessArticle

Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies

by Claus-Dieter Mayer, Soizick Magon de La Giclais, Fozan Alsehly and Stefan Hoppler

Genes 2020, 11(5), 538; https://doi.org/10.3390/genes11050538 - 11 May 2020

Cited by 13 | Viewed by 3911

Abstract

Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and [...] Read more.

Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and may potentially be correlated with indicators of cancer progression. We carried out a meta-analysis of carefully selected publicly available gene expression data sets with paired tumor biopsy and adjacent matched normal tissues from colorectal cancer patients. Our meta-analysis confirms that among the four human LEF/TCF genes, LEF1 and TCF7 are preferentially expressed in tumor biopsies, while TCF7L2 and TCF7L1 in normal control tissue. We also confirm positive correlation of LEF1 and TCF7 expression with hallmarks of active Wnt signaling (i.e., AXIN2 and LGR5). We are able to correlate differential LEF/TCF gene expression with distinct transcriptomes associated with cell adhesion, extracellular matrix organization, and Wnt receptor feedback regulation. We demonstrate here in human colorectal tumor sample correlation of altered LEF/TCF gene expression with quantitatively and qualitatively different transcriptomes, suggesting LEF/TCF-specific transcriptional regulation of Wnt target genes relevant for cancer progression and survival. This bioinformatics analysis provides a foundation for future more detailed, functional, and molecular analyses aimed at dissecting such functional differences. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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15 pages, 2602 KiB

Open AccessCommunication

Vulpinic Acid Controls Stem Cell Fate toward Osteogenesis and Adipogenesis

by Sang Ah Yi, Ki Hong Nam, Sil Kim, Hae Min So, Rhim Ryoo, Jeung-Whan Han, Ki Hyun Kim and Jaecheol Lee

Genes 2020, 11(1), 18; https://doi.org/10.3390/genes11010018 - 23 Dec 2019

Cited by 8 | Viewed by 3530

Abstract

Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, Pulveroboletus ravenelii controls the [...] Read more.

Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, Pulveroboletus ravenelii controls the cell fate of mesenchymal stem cells and preadipocytes by inducing the acetylation of histone H3 and α-tubulin, respectively. The treatment of 10T1/2 mesenchymal stem cells with vulpinic acid increased the expression of Wnt6, Wnt10a, and Wnt10b, which led to osteogenesis inhibiting the adipogenic lineage commitment, through the upregulation of H3 acetylation. By contrast, treatment with vulpinic acid promoted the terminal differentiation of 3T3-L1 preadipocytes into mature adipocytes. In this process, the increase in acetylated tubulin was accompanied, while acetylated H3 was not altered. As excessive generation of adipocytes occurs, the accumulation of lipid drops was not concentrated, but dispersed into a number of adipocytes. Consistently, the expressions of lipolytic genes were upregulated and inflammatory factors were downregulated in adipocytes exposed to vulpinic acid during adipogenesis. These findings reveal the multiple actions of vulpinic acid in two stages of differentiation, promoting the osteogenesis of mesenchymal stem cells and decreasing hypertrophic adipocytes, which can provide experimental evidence for the novel metabolic advantages of vulpinic acid. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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13 pages, 1303 KiB

Open AccessArticle

Wnt-11 Expression Promotes Invasiveness and Correlates with Survival in Human Pancreatic Ductal Adeno Carcinoma

by Dafydd A. Dart, Damla E Arisan, Sioned Owen, Chunyi Hao, Wen G. Jiang and Pinar Uysal-Onganer

Genes 2019, 10(11), 921; https://doi.org/10.3390/genes10110921 - 11 Nov 2019

Cited by 11 | Viewed by 3419

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study aimed to elucidate these aspects first in vitro and then in a clinical setting in vivo. Molecular analyses of Wnt-11 expression as well as other biomarkers involved qRT-PCR, RNA-seq and siRNA. Proliferation was measured by MTT; invasiveness was quantified by Boyden chamber (Matrigel) assay. Wnt-11 mRNA was present in three different human PDAC cell lines. Wnt-11 loss affected epithelial-mesenchymal transition and expression of neuronal and stemness biomarkers associated with metastasis. Indeed, silencing Wnt-11 in Panc-1 cells significantly inhibited their Matrigel invasiveness without affecting their proliferative activity. Consistently with the in vitro data, human biopsies of PDAC showed significantly higher Wnt-11 mRNA levels compared with matched adjacent tissues. Expression was significantly upregulated during PDAC progression (TNM stage I to II) and maintained (TNM stages III and IV). Wnt-11 is expressed in PDAC in vitro and in vivo and plays a significant role in the pathophysiology of the disease; this evidence leads to the conclusion that Wnt-11 could serve as a novel, functional biomarker PDAC. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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Review

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20 pages, 2325 KiB

Open AccessReview

The Canonical Wnt Pathway as a Key Regulator in Liver Development, Differentiation and Homeostatic Renewal

by Sebastian L. Wild, Aya Elghajiji, Carmen Grimaldos Rodriguez, Stephen D. Weston, Zoë D. Burke and David Tosh

Genes 2020, 11(10), 1163; https://doi.org/10.3390/genes11101163 - 30 Sep 2020

Cited by 18 | Viewed by 8446

Abstract

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of [...] Read more.

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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18 pages, 1322 KiB

Open AccessReview

Wnt/β-catenin Signaling in Tissue Self-Organization

by Kelvin W. Pond, Konstantin Doubrovinski and Curtis A. Thorne

Genes 2020, 11(8), 939; https://doi.org/10.3390/genes11080939 - 14 Aug 2020

Cited by 23 | Viewed by 5988

Abstract

Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are [...] Read more.

Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are how these patterns are generated and maintained during tissue homeostasis and regeneration. Though fascinating scientists for generations, these ideas remain poorly understood. Today, it is apparent that the Wnt/β-catenin pathway plays a central role in tissue patterning. Wnt proteins are small diffusible morphogens which are essential for cell type specification and patterning of tissues. In this review, we highlight several mechanisms described where the spatial properties of Wnt/β-catenin signaling are controlled, allowing them to work in combination with other diffusible molecules to control tissue patterning. We discuss examples of this self-patterning behavior during development and adult tissues’ maintenance. The combination of new physiological culture systems, mathematical approaches, and synthetic biology will continue to fuel discoveries about how tissues are patterned. These insights are critical for understanding the intricate interplay of core patterning signals and how they become disrupted in disease. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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11 pages, 1677 KiB

Open AccessReview

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

by Christin C. Anthony, David J. Robbins, Yashi Ahmed and Ethan Lee

Genes 2020, 11(8), 886; https://doi.org/10.3390/genes11080886 - 4 Aug 2020

Cited by 80 | Viewed by 8007

Abstract

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. [...] Read more.

Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway—nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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25 pages, 1238 KiB

Open AccessReview

Glia and Neural Stem and Progenitor Cells of the Healthy and Ischemic Brain: The Workplace for the Wnt Signaling Pathway

by Tomas Knotek, Lucie Janeckova, Jan Kriska, Vladimir Korinek and Miroslava Anderova

Genes 2020, 11(7), 804; https://doi.org/10.3390/genes11070804 - 16 Jul 2020

Cited by 18 | Viewed by 4705

Abstract

Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or [...] Read more.

Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or even reverse the negative effects of ischemic brain injury. In this review, we provide the current knowledge of Wnt signaling in the adult CNS, its status in diverse cell types, and the Wnt pathway’s impact on the properties of NS/PCs and glial cells in the context of ischemic injury. Finally, we summarize promising strategies that might be considered for stroke therapy, and we outline possible future directions of the field. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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19 pages, 1114 KiB

Open AccessReview

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

by Soniya A. Malik, Kavindiya Modarage and Paraskevi Goggolidou

Genes 2020, 11(5), 496; https://doi.org/10.3390/genes11050496 - 30 Apr 2020

Cited by 23 | Viewed by 5077

Abstract

Chronic kidney disease (CKD) encompasses a group of diverse diseases that are associated with accumulating kidney damage and a decline in glomerular filtration rate (GFR). These conditions can be of an acquired or genetic nature and, in many cases, interactions between genetics and [...] Read more.

Chronic kidney disease (CKD) encompasses a group of diverse diseases that are associated with accumulating kidney damage and a decline in glomerular filtration rate (GFR). These conditions can be of an acquired or genetic nature and, in many cases, interactions between genetics and the environment also play a role in disease manifestation and severity. In this review, we focus on genetically inherited chronic kidney diseases and dissect the links between canonical and non-canonical Wnt signalling, and this umbrella of conditions that result in kidney damage. Most of the current evidence on the role of Wnt signalling in CKD is gathered from studies in polycystic kidney disease (PKD) and nephronophthisis (NPHP) and reveals the involvement of β-catenin. Nevertheless, recent findings have also linked planar cell polarity (PCP) signalling to CKD, with further studies being required to fully understand the links and molecular mechanisms. Full article

(This article belongs to the Special Issue Wnt Signaling in Development, Regeneration and Cancer)

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