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

Wild, Sebastian L.; Elghajiji, Aya; Rodrı́guez, Carmen; Weston, Stephen D.; Burke, Zoë D.; Tosh, David

doi:10.3390/genes11101163

Cited by 22 publications

(16 citation statements)

References 119 publications

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“…Signaling by the secreted glycolipoprotein factors of the Wnt family via β-catenin, as the transcription co-activator, regulates multiple developmental processes during embryogenesis and adult homeostasis through its critical role in cell growth, differentiation, and cellular metabolism [ 151 , 152 ]. Once the Wnt signaling molecule presents itself, it binds to a Frizzled receptor and triggers the activation of the co-receptor LRP, leading to a transfer of the biological signal to a Disheveled (Dvl) protein within the cytoplasm.…”

Section: Curcumin: Impacts On Multiple Cellular Signaling Pathways In Hormone-independent Breast Cancermentioning

confidence: 99%

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

Farghadani

Naidu

2021

Cancers

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Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.

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Section: Curcumin: Impacts On Multiple Cellular Signaling Pathways In Hormone-independent Breast Cancermentioning

confidence: 99%

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

Farghadani

Naidu

2021

Cancers

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“…The Wnt/β-catenin signaling cascade starts with the binding of Wnt ligands to their cell surface Frizzled receptors and low-density lipoprotein co-receptors, leading to the degradation of the multiprotein β-catenin destruction complex and finally resulting in β-catenin nuclear translocation and consequent target gene transcription [ 155 , 156 ]. Pharmacological inhibition of β-catenin with PKF118-310 and ICG-001 was shown to prevent and reverse dermal fibrosis by ameliorating skin thickness and reducing myofibroblast counts ex vivo [ 157 ], while in SSc patients, local treatment of affected skin with the β-catenin inhibitor C82 reduced a specific cluster of genes known to be associated with SSc but did not ameliorate the modified Rodnan skin score (mRSS) [ 158 ].…”

Section: Main Molecular Pathways Driving Myofibroblast Differentiation From Vascular Wall Residing Cells In Systemic Sclerosis and Relatementioning

confidence: 99%

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Romano

Rosa

Fioretto

et al. 2021

Life

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In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.

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“…Another highly conserved transduction pathway known to be involved in several important biological processes, such as liver development, vascular and hepatic differentiation, and tissue homeostasis is the Wnt-/β-catenin signaling pathway (Decaens et al, 2008 ; Daneman et al, 2009 ; Wild et al, 2020 ). In the liver vasculature, Wnt2 was identified as an LSEC-associated molecule with autocrine growth effects (Klein et al, 2008 ; Geraud et al, 2010 ), and also as an angiocrine regulator of liver regeneration (Ding et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

et al. 2021

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Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

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

Cited by 22 publications

References 119 publications

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

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