scholarly journals Extracellular Matrix (ECM) Activates β-catenin Signaling in Uterine Fibroids

Reproduction ◽  
2018 ◽  
Author(s):  
Yi-An Ko ◽  
Muhammad Jamaluddin ◽  
Mariam Adebayo ◽  
Preety Bajwa ◽  
Rodney Scott ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Uterine Fibroids ◽  
Wild Type ◽  
Mutational Status ◽  
The Status ◽  
Wnt Inhibitor ◽  
Med12 Gene ◽  
New Treatments

κΩΨ¥–€™±≈‰ greater than > less than Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/β-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wild type fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium samples. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild type fibroids. Liquid chromatography-mass spectrometry (LC-MS), western blotting, and immunohistochemistry were used to monitor the expression of β-catenin. We showed that β-catenin expression was increased in fibroids compared to the adjacent myometrium samples. However, β-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on β-catenin expression and revealed increased levels of β-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed that β-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate β-catenin expression in fibroids, providing an attractive avenue for developing new treatments for this disease.

scholarly journals Casein Kinase 1α as a Regulator of Wnt-Driven Cancer

2020 ◽  
Vol 21 (16) ◽  
pp. 5940
Author(s):  
Chen Shen ◽  
Anmada Nayak ◽  
Ricardo A. Melendez ◽  
Daniel T. Wynn ◽  
Joshua Jackson ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Therapeutic Index ◽  
Casein Kinase ◽  
Pathway Activity ◽  
Physiological Importance ◽  
Disease States ◽  
Wnt Inhibitor

Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.

Epigenetic regulation of the Wnt-signaling pathway in CIMP-H BRAFV600E mCRC.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 110-110
Author(s):  
Hey Min Lee ◽  
Stefania Napolitano ◽  
Van K. Morris ◽  
Kunal Rai ◽  
John Paul Y.C. Shen ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Braf Mutation ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Methylation Profile ◽  
Brafv600e Mutation ◽  
Wild Type ◽  
Mutation Status ◽  
Pathway Activation ◽  
Apc Mutation

110 Background: BRAFV600E mutation identifies mCRC patients with poor prognosis with only little benefit from standard therapy. Analysis from TCGA revealed that 89% of BRAFV600E CRC tumors were associated with a high CpG island methylator phenotype (CIMP-H), which may result in epigenetic silencing of tumor suppressor genes, while only 29% of BRAF wild-type tumors are CIMP-H. In this study, we define key pathways regulated by global DNA hypermethylation in the context of BRAFV600E mutation. Methods: We analyzed the TCGA Illumina 450k array methylation datasets and RNA-sequencing datasets for 97 CIMP-H CRC tumors (27 BRAFV600E; 69 BRAF WT) identified by five universal CIMP annotations ( p14, p16, MLH1, MINT1, MINT2, MINT31). We defined differential methylation profile according to BRAF mutation status and calculated Spearman correlation between methylation and gene expression to identify CIMP-H BRAF-associated genes. Next, pathways enriched with CIMP-H BRAFV600E tumors were defined using PANTHER pathway analysis. Additionally, β-catenin IHC were conducted on 145 MD Anderson CRC patient samples and compared by CIMP and BRAF status. Results: BRAF mutation is associated with lower rates of APC mutation as has previously been shown (32%, 82%). We identified 6,097 differentially methylated probes by BRAF mutation status (FDR = 10-4), and as expected, our data suggests a higher methylation profile in BRAFV600E mutated tumors compared to BRAF WT. Intriguingly, CIMP-H BRAF-associated genes showed enrichment in the Wnt-signaling and cadherin signaling pathways ( p< 0.0001 (FDR < 0.0001)). Despite the epigenetic Wnt-signaling, nuclear β-catenin expression (as a measure of Wnt activity) in CIMP-H and BRAF tumors remains lower than for non-CIMP, and BRAF wild-type ( p= 0.0003 for comparison of CIMP). Conclusions: Genes under methylation regulation in the BRAF-mutant context showed enrichment in Wnt-signaling pathway. Since BRAFV600E CRC tumors have a low association with APC mutation, this data suggests role of epigenetic regulation of the Wnt-pathway activation. However, as measured by nuclear β-catenin, Wnt activation in these tumors is not as high as traditional APC-mutated CRC tumors. CIMP-H tumors with BRAFV600E mutation is a unique subset of CRC tumor that have Wnt-pathway activation regulated by epigenetic modifications more than a β-catenin activation.

scholarly journals Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3446
Author(s):  
Stefan Koch
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Treatment Options ◽  
Wnt Signaling Pathway ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 37-49 ◽  
Author(s):  
J.N. Maloof ◽  
J. Whangbo ◽  
J.M. Harris ◽  
G.D. Jongeward ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Hox Genes ◽  
Wnt Signaling Pathway ◽  
Beta Catenin ◽  
Hox Gene ◽  
C Elegans ◽  
Neuroblast Migration ◽  
Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

scholarly journals Replicating Adenoviruses That Target Tumors with Constitutive Activation of the wnt Signaling Pathway

2001 ◽  
Vol 75 (6) ◽  
pp. 2857-2865 ◽  
Author(s):  
Michele Brunori ◽  
Maddalena Malerba ◽  
Haruhiko Kashiwazaki ◽  
Richard Iggo
Keyword(s):  
Wnt Signaling ◽  
Cancer Cells ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Lung Model ◽  
Colorectal Tumors ◽  
Colon Tumors ◽  
Treat All

ABSTRACT Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncogenic defects. Selectively replicating viruses have a major advantage over nonreplicating viruses to target these defects because the therapeutic effect of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating adenoviruses that express the viral E1B and E2 genes from promoters controlled by the Tcf4 transcription factor. Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and β-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but not all, cell lines with activation of the wnt pathway. Viruses with Tcf regulation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells and WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable β-catenin mutant into normal fibroblasts renders the cells permissive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces the inflammatory response in a rodent lung model in vivo. Replicating adenoviruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but additional changes will be required to produce a virus that can be used to treat all colon tumors.

Inhibition of Wnt Pathway Signaling by Thalidomide and Revlimid: Studies in a Drosophila Model System.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3356-3356
Author(s):  
A. Keith Stewart ◽  
Yuan Xiao Zhu ◽  
Maryan Yahyapour ◽  
Armen Manoukian ◽  
Sam E. Scanga
Keyword(s):  
Wnt Signaling ◽  
Cell Lines ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Cellular Proliferation ◽  
Wnt Signaling Pathway ◽  
Myeloma Cell ◽  
Lacz Expression ◽  
Western Blots ◽  
Drosophila Model

Abstract High throughput sequencing, gene expression profiling and protein biochemistry in myeloma have all consistently revealed elevated expression of wnt signaling pathways in malignant plasma cells. Indeed, downregulation of the Wnt pathway in myeloma cells has recently been shown to inhibit myeloma cellular proliferation. Preliminary pharmacogenomic studies have also suggested that hyperactivation of the wnt signaling antagonist DKK-1 is associated with response to the immunomodulators thalidomide and revlimid. The mechanism of action for these therapeutically active drugs is however by no means clear as multiple biologic consequences of treatment have been proposed. We report here use of a drosophila model to examine wnt signaling inhibition by these pharmaceuticals. We employed a unique drosophila larval imaginal disc culture system in which wnt pathway activity is monitored through control of LacZ expression by the distalless promoter. In this system 10uM of both thalidomide and revlimid reproducibly inhibit lacZ expression when compared with vehicle controls. Western blots of larva confirmed downregulation of expression of armadillo (the drosophila b-catenin homologue) by both drugs but particularly revlimid. Lithium Chloride is an inhibitor of the drosphila GSK3b homologue shaggy and thus mimics wnt signaling by stabilizing b-catenin. The effect of Lithium could not be overcome by thalidomide or revlimid indicating that the action of these drugs is upstream of shaggy (or GSK3). Next we employed a fly transgenic for wingless which is embryonic lethal. By adding either drug to larval culture medium the lethality of wingless expression was reversed. Indeed drosophila embryos fed thalidomide exhibited developmental plate abnormalities. We next sought evidence that similar effects were evident in revlimid treated human myeloma. As previously reported most myeloma cell lines studied expressed b-catenin and this protein was downregulated by revlimid treatment of human myeloma cell lines co-incident with inhibition of growth as measured by MTT assay. We sought, but failed to find evidence of up-regulation of the wnt signaling pathway antagonist DKK-1 using an ELISA assay on pre and post treatment serum samples in patients responding to thalidomide.The implications of wnt signaling inhibition as a primary or secondary readout of therapeutic efficiency in MM may be of substantial importance in subsequent design of drug therapies or combination therapies.

scholarly journals Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

2002 ◽  
Vol 22 (4) ◽  
pp. 1172-1183 ◽  
Author(s):  
Eek-hoon Jho ◽  
Tong Zhang ◽  
Claire Domon ◽  
Choun-Ki Joo ◽  
Jean-Noel Freund ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Pathway ◽  
Genomic Sequence ◽  
Wnt Signaling Pathway ◽  
Genomic Region ◽  
Negative Regulator ◽  
Mobility Shift ◽  
Specific Expression

ABSTRACT Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2. Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals Roles of the Wnt Signaling Pathway in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 7 ◽  
Author(s):  
Jing Xie ◽  
Li Huang ◽  
You-Guang Lu ◽  
Da-Li Zheng
Keyword(s):  
Squamous Cell Carcinoma ◽  
Wnt Signaling ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Neck Squamous Cell Carcinoma ◽  
Upstream Gene

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck tumor. It is a high incidence malignant tumor associated with a low survival rate and limited treatment options. Accumulating conclusions indicate that the Wnt signaling pathway plays a vital role in the pathobiological process of HNSCC. The canonical Wnt/β-catenin signaling pathway affects a variety of cellular progression, enabling tumor cells to maintain and further promote the immature stem-like phenotype, proliferate, prolong survival, and gain invasiveness. Genomic studies of head and neck tumors have shown that although β-catenin is not frequently mutated in HNSCC, its activity is not inhibited by mutations in upstream gene encoding β-catenin, NOTCH1, FAT1, and AJUBA. Genetic defects affect the components of the Wnt pathway in oral squamous cell carcinoma (OSCC) and the epigenetic mechanisms that regulate inhibitors of the Wnt pathway. This paper aims to summarize the groundbreaking discoveries and recent advances involving the Wnt signaling pathway and highlight the relevance of this pathway in head and neck squamous cell cancer, which will help provide new insights into improving the treatment of human HNSCC by interfering with the transcriptional signaling of Wnt.

scholarly journals Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling

2021 ◽  
Vol 13 ◽  
Author(s):  
Soledad Galli ◽  
Stefka H. Stancheva ◽  
Tom Dufor ◽  
Alasdair J. Gibb ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Complete Recovery ◽  
Adult Brain ◽  
Inhibitory Synapses ◽  
Medium Spiny Neurons ◽  
Dkk1 Expression ◽  
Synapse Degeneration

Synapse degeneration in the striatum has been associated with the early stages of Parkinson’s and Huntington’s diseases (PD and HD). However, the molecular mechanisms that trigger synaptic dysfunction and loss are not fully understood. Increasing evidence suggests that deficiency in Wnt signaling triggers synapse degeneration in the adult brain and that this pathway is affected in neurodegenerative diseases. Here, we demonstrate that endogenous Wnt signaling is essential for the integrity of a subset of inhibitory synapses on striatal medium spiny neurons (MSNs). We found that inducible expression of the specific Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum leads to the loss of inhibitory synapses on MSNs and affects the synaptic transmission of D2-MSNs. We also discovered that re-activation of the Wnt pathway by turning off Dkk1 expression after substantial loss of synapses resulted in the complete recovery of GABAergic and dopamine synapse number. Our results also show that re-activation of the Wnt pathway leads to a recovery of amphetamine response and motor function. Our studies identify the Wnt signaling pathway as a potential therapeutic target for restoring neuronal circuits after synapse degeneration.

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