The regulatory roles of Notch in osteocyte differentiation via the crosstalk with canonical Wnt pathways during the transition of osteoblasts to osteocytes

Bone ◽  
2018 ◽  
Vol 108 ◽  
pp. 165-178 ◽  
Author(s):  
Jin Shao ◽  
Yinghong Zhou ◽  
Yin Xiao
Keyword(s):  
Wnt Pathways ◽  
Canonical Wnt

scholarly journals A Non-canonical Wnt Signature Correlates With Lower Survival in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Pablo Astudillo
Keyword(s):  
Gastric Cancer ◽  
Protein Expression ◽  
Wnt Signaling Pathway ◽  
Mesenchymal Cell ◽  
Gene And Protein Expression ◽  
Cancer Initiation ◽  
Wnt Pathways ◽  
Canonical Wnt ◽  
Mesenchymal Cell Marker ◽  
Shared Gene

Genetic evidence suggests a role for the Wnt/β-catenin pathway in gastric cancer. However, Wnt5a, regarded as a prototypical non-canonical Wnt ligand, has also been extensively associated with this disease. Therefore, the roles of the Wnt signaling pathway in gastric cancer initiation and progression, and particularly the precise mechanisms by which the non-canonical Wnt pathway might promote the development and progression of gastric cancer, are not entirely well understood. This article analyzes publicly available gene and protein expression data and reveals the existence of a WNT5A/FZD2/FZD7/ROR2 signature, which correlates with tumor-infiltrating and mesenchymal cell marker expression. High expression of FZD7 and ROR2 correlates with a shared gene and protein expression profile, which in turn correlates with poor prognosis. In summary, the findings presented in this article provide an updated view of the relative contributions of the Wnt/β-catenin and non-canonical Wnt pathways in gastric cancer.

Activation of Non-Canonical Wnt Pathway in Human Mesenchymal Cells Affects Osteogenic Differentiation: A Potential Target in Multiple Myeloma Microenvironment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2742-2742 ◽  
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Paola Storti ◽  
Gaetano Donofrio ◽  
Marina Bolzoni ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Wnt Signaling ◽  
Osteogenic Differentiation ◽  
Wnt Signaling Pathway ◽  
Inhibitory Effect ◽  
Canonical Wnt Signaling ◽  
Wnt Pathways ◽  
Canonical Wnt ◽  
Wnt Signal ◽  
Alkaline Phosphatase Expression

Abstract Osteoblast suppression is the hallmark of Multiple Myeloma (MM) osteolytic bone lesions mainly due to the capacity of MM cells to inhibit the osteogenic differentiation of bone marrow (BM) mesenchymal cells (MSC). Many evidences suggest that Wnt signaling is critically involved in the regulation of osteoblast formation. Recently, in murine osteoprogenitor cells and in MM mouse models it has been shown that activation of canonical Wnt pathway stimulate osteoblast formation and blunts MM-induced bone destruction. In this study we have investigated whether modulation of both canonical and noncanonical Wnt signaling pathway may affect osteogenic differentiation of human MSC and counterbalance the suppressive effect of MM cells. First we checked the potential expression of Wnt activators and inhibitors by human MSC and osteoprogenitor cells (PreOB) by gene arrays. We found that both cells expressed the activator of non-canonical Wnt pathways Wnt5a but lack of express the main activators of canonical Wnt signaling as Wnt1, Wnt3a and Wnt8. The presence of the Wnt5a receptor FZD2 and FZD5 was also detected in both cells as well as that of FZD3, FZD6 and FDZ7 and the Wnt canonical co-receptors LRP5 and LRP6. On the other hand we found that both inhibitors of canonical and non-canonical Wnt pathways DKK-1 and sFRP-1 were expressed by MSC. Secondly, activation of either canonical or non-canonical Wnt signaling pathway by Wnt3a and Wnt5a treatment respectively was performed in human MSC to evaluate the effect on osteogenic differentiation and the expression of osteoblast related markers (Collagen I, Osteocalcin and Alkaline Phosphatase). We found that Wnt5a treatment but not Wnt3a significantly increased the early osteogenic differentiation and the expression of alkaline phosphatase in MSC. Consistently in a co-culture system with MM cells Wnt5a treatment blunted, at least in part, the inhibitory effect of MM cells on alkaline phosphatase expression by MSC and PreOB. To go further inside, we evaluated in both primary human BM MSC and the human MSC cell line HS-5 the effect of either the activation of non-canonical Wnt signaling by Wnt5a overexpression using a lentivirus vector or the Wnt5a suppression using siRNA. Wnt5a over-expression in MSC induced the activation of Wnt/Ca++ non-canonical pathway as demonstrated by the increase of Wnt5a secretion and phospho-PKC expression detected by westernblot analysis. Consequently to non-canonical Wnt signal activation we found a significant increase of alkaline phosphatase expression by MSC cells as well as of their osteogenic differentiation. Interestingly, analyzing the gene expression profile by microarray, we found that Wnt5a overexpression in MSC also affects the expression of chemokines, inflammatory cytokines and pro-angiogenic molecules. In conclusion our data indicate that activation of non-canonical Wnt signal pathway may represent a potential target in MM microenvironment to counterbalance the inhibitory effect of MM cells on osteogenic differentiation of human MSC.

scholarly journals Wnt3a signal pathways activate MyoD expression by targeting cis-elements inside and outside its distal enhancer

2015 ◽  
Vol 35 (2) ◽  
Author(s):  
Yu Chih Pan ◽  
Xiao Wen Wang ◽  
Han Feng Teng ◽  
Yi Ju Wu ◽  
Hsuan Chia Chang ◽  
...  
Keyword(s):  
Signal Pathways ◽  
Cis Elements ◽  
Distal Enhancer ◽  
Wnt Pathways ◽  
Canonical Wnt ◽  
Myod Expression

We found that Wnt3a can directly activate MyoD expression through targeting cis-elements in the distal enhancer and in the upstream −8 to −9k region. A novel Pax3/Pax7-involved pathway and both canonical and non-canonical Wnt pathways are involved in this activation.

scholarly journals Dual modulation of human hepatic zonation via canonical and non-canonical Wnt pathways

2017 ◽  
Vol 49 (12) ◽  
pp. e413-e413 ◽  
Author(s):  
Laura McEnerney ◽  
Kara Duncan ◽  
Bo-Ram Bang ◽  
Sandra Elmasry ◽  
Meng Li ◽  
...  
Keyword(s):  
Wnt Pathways ◽  
Canonical Wnt

scholarly journals Targeting Casein Kinase 1 (CK1) in Hematological Cancers

2020 ◽  
Vol 21 (23) ◽  
pp. 9026
Author(s):  
Pavlína Janovská ◽  
Emmanuel Normant ◽  
Hari Miskin ◽  
Vítězslav Bryja
Keyword(s):  
Clinical Trials ◽  
Therapeutic Potential ◽  
Clinical Stage ◽  
Casein Kinase ◽  
Lymphocytic Leukemia ◽  
Casein Kinase 1 ◽  
Hematological Cancers ◽  
Recent Developments ◽  
Wnt Pathways ◽  
Canonical Wnt

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

scholarly journals miR-195-5p Regulates Hair Follicle Inductivity of Dermal Papilla Cells by Suppressing Wnt/β-Catenin Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ningxia Zhu ◽  
Keng Huang ◽  
Yang Liu ◽  
Huan Zhang ◽  
En Lin ◽  
...  
Keyword(s):  
Hair Follicle ◽  
Posttranscriptional Regulation ◽  
Dermal Papilla ◽  
Vital Role ◽  
Early Passage ◽  
Dermal Papilla Cells ◽  
Key Factor ◽  
Late Passage ◽  
Wnt Pathways ◽  
Canonical Wnt

Dermal papilla (DP) cells play a vital role in hair follicle (HF) development and postnatal hair cycling. However, the abilities are lost on further culture. Recent studies have demonstrated significant influences of posttranscriptional regulation by microRNA (miRNA) on HF development. The current study aims to investigate how miRNAs regulate Wnt/β-catenin to control HF inductivity of DP cells by performing microarray analysis in early- and late-passage DP cells and transfecting with miRNAs inhibitor or mimic. Results showed early-passage DP cells strongly expressed miRNAs related to inhibition of noncanonical Wnt pathways. In late-passage DP cells, miRNAs capable of inhibiting the canonical Wnt/β-catenin pathway were upregulated, in addition to the miRNAs targeting the noncanonical Wnt pathway. Moreover, we verified that β-catenin expression was downregulated by miR-195-5p overexpression in dose manner. Meanwhile LRP6 expression was downregulated in both protein and mRNA as well as the genes involved in the hair inductivity of DP cells. These results suggest that the appearance of miRNAs that suppress the Wnt/β-catenin pathway may be responsible for the loss of ability of DP cells in culture and miR-195-5p is the potential key factor involved in regulating HF inductivity of DP cells.

scholarly journals Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

2014 ◽  
Vol 112 (1) ◽  
pp. 166-171 ◽  
Author(s):  
Wenyan Li ◽  
Jingfang Wu ◽  
Jianming Yang ◽  
Shan Sun ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Lineage Tracing ◽  
Supporting Cells ◽  
Hearing Recovery ◽  
Wnt Pathways ◽  
Notch Inhibition ◽  
Canonical Wnt ◽  
G Protein Coupled

The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

scholarly journals Frizzled receptors in tumors, focusing on signaling, roles, modulation mechanisms, and targeted therapies

2020 ◽  
Author(s):  
Yu Sun ◽  
Wei Wang ◽  
Chenghai Zhao
Keyword(s):  
Targeted Therapies ◽  
Tumor Development ◽  
Fragility Fractures ◽  
Mouse Tumor ◽  
Oncogenic Pathway ◽  
Cellular Context ◽  
Frizzled Receptors ◽  
Wnt Pathways ◽  
Canonical Wnt ◽  
Cultured Tumor Cells

Wnt molecules play crucial roles in development and adult homeostasis through their receptors Frizzled proteins (Fzds). Fzds mediate canonical β-catenin pathway and various non-canonical β-catenin-independent pathways. Aberrant Fzd signaling is involved in many diseases including cancer. Wnt/β-catenin is a well-established oncogenic pathway involved in almost every aspects of tumor development. However, Fzd-mediated non-canonical Wnt pathways function as both tumor promoters and tumor suppressors depending on cellular context. Fzd-targeted therapies have proven to be effective on cultured tumor cells, tumor cell xenografts, mouse tumor models and patient-derived xenografts (PDX). Moreover, Fzd-targeted therapies synergize with chemotherapy in preclinical models. However, the occurrence of fragility fractures in patients treated with Fzd-targeted agents such as OMP-54F28 and OMP-18R5 limits the development of this combination. Along with new insights on signaling, roles, and modulation mechanisms of Fzds in human tumors, more Fzd-related therapeutic targets will be developed.

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