Abstract P108: Wnt Pathway Gene Expression is Associated With Greater Arterial Stiffness

Background Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years). Methods and Results Gene expression was assessed using a custom Nanostring nC ounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial‐ankle pulse‐wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse‐wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway ( APC ), glycogen synthase kinase 3β ( GSK 3B ), and transcription factor 4 ( TCF 4 ) were significantly associated with arterial stiffness ( P <0.05 for all). When entered into a single model, APC and TCF 4 expression remained independently associated with arterial stiffness ( P =0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse‐wave velocity. Conclusions The current study establishes a novel association between in vivo expression of the Wnt pathway genes, APC and TCF 4 , with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.

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

Development ◽

10.1242/dev.126.1.37 ◽

1999 ◽

Vol 126 (1) ◽

pp. 37-49 ◽

Cited By ~ 9

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.

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Novel mechanism linking noncanonical Wnt ligand induction to suppression of colorectal cancer cell proliferation.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.648 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 648-648

Author(s):

Donald Peter Braun ◽

Bani M Fagla ◽

Irshad Ali

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Cell Proliferation ◽

Wnt Pathway ◽

Fold Increase ◽

Canonical Pathway ◽

Unexpected Finding ◽

Cancer Cell Proliferation ◽

Pathway Gene ◽

Proliferation And Differentiation

648 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation. A central pathway in the control of proliferation and differentiation is the Wnt pathway. Wnt function is mediated by a canonical pathway (CP) which utilizes β-catenin and stimulates cell proliferation, and a non-canonical pathway (NCP) independent of β-catenin involved with differentiation. Studies suggest that dysfunctional Wnt signaling results from imbalance of CP components. The possibility that modulation of NCP components are involved in this process has not been studied comprehensively. Given their importance in constraining CP signaling and proliferation, the purpose of this study was to determine the capacity of NCP components to suppress human colorectal cancer (CRC) proliferation. Methods: Short term, primary CRC lines were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of the CP, Dkk1, an inhibitor of the CP, and IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion. CRC proliferation and Wnt pathway gene expression were determined by MTS assays and quantitative gene expression respectively. Results: Unexpectedly, CRC proliferation was inhibited significantly (p<0.01) by LiCl and stimulated modestly (ns) by Dkk1. This was associated with a 20 fold increase in gene expression for the NCP ligand, Wnt9A. LiCl treated cells incubated with IWP-2 reversed the unexpected LiCl-mediated suppression of CRC proliferation. Conclusions: The unexpected finding that LiCl suppresses proliferation and Dkk1 has the opposite effect indicate dysregulation of the Wnt pathway in CRC. Further support for this hypothesis is the fact that Wnt 9A, an NCP ligand is increased by LiCl in CRC, an effect that is not expected in non-malignant cells. That IWP-2, a pan Wnt ligand secretion inhibitor reverses these effects is consistent with these observations. This study is the first to demonstrate a correlation between NCP ligand induction and suppression of CRC proliferation and suggests that control of CRC proliferation may be achieved in patients by modalities that activate the NCP Wnt pathway.

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Wnt pathway gene expression and association with clinicopathologic characteristics in endometrial cancer – An analysis of The Cancer Genome Atlas (TCGA)

Gynecologic Oncology ◽

10.1016/j.ygyno.2013.04.267 ◽

2013 ◽

Vol 130 (1) ◽

pp. e89 ◽

Cited By ~ 1

Author(s):

T. Dellinger ◽

C. Warden ◽

E. Han ◽

M. Wakabayashi

Keyword(s):

Gene Expression ◽

Endometrial Cancer ◽

Wnt Pathway ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Clinicopathologic Characteristics ◽

Pathway Gene ◽

Cancer Genome Atlas ◽

Genome Atlas

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13-P020 Complex and dynamic patterns of Wnt pathway gene expression in the developing chick forebrain

Mechanisms of Development ◽

10.1016/j.mod.2009.06.493 ◽

2009 ◽

Vol 126 ◽

pp. S200-S201

Author(s):

Robyn Quinlan ◽

Manuela Graf ◽

Ivor Mason ◽

Andrew Lumsden ◽

Clemens Kiecker

Keyword(s):

Gene Expression ◽

Wnt Pathway ◽

Pathway Gene ◽

Chick Forebrain ◽

Dynamic Patterns

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The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models

Cancer Letters ◽

10.1016/j.canlet.2019.09.009 ◽

2020 ◽

Vol 473 ◽

pp. 186-197 ◽

Cited By ~ 17

Author(s):

Betty Y. Tam ◽

Kevin Chiu ◽

Heekyung Chung ◽

Carine Bossard ◽

John Duc Nguyen ◽

...

Keyword(s):

Gene Expression ◽

Gastrointestinal Cancer ◽

Wnt Pathway ◽

Pathway Gene ◽

Cancer Models ◽

Anti Tumor Activity

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Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-07-1588 ◽

2008 ◽

Vol 14 (4) ◽

pp. 995-1001 ◽

Cited By ~ 22

Author(s):

Paloma Ortega ◽

Alberto Morán ◽

Carmen de Juan ◽

Cristina Frías ◽

Susana Hernández ◽

...

Keyword(s):

Gene Expression ◽

Microsatellite Instability ◽

Wnt Pathway ◽

Colorectal Cancers ◽

Pathway Gene ◽

E Cadherin

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P085 Expression profiling of Wnt pathway genes in colon biopsies of patients with Ulcerative Colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.214 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S186-S186

Author(s):

C Lu ◽

D Shah ◽

A Wijnands ◽

B Oldenburg ◽

W C Yeh ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Wnt Signaling ◽

Wnt Pathway ◽

Target Genes ◽

Expression Patterns ◽

Critical Role ◽

Epithelial Regeneration ◽

Pathway Gene ◽

Wnt Signal

Abstract Background There is an increasing demand of agents that can promote mucosal healing in Inflammatory Bowel Disease (IBD). Wnt/β-catenin signaling plays a critical role in epithelial regeneration and repair, and stimulating regeneration in the damaged epithelium by modulating Wnt signaling has been suggested as a potential treatment option for IBD. To guide development of Wnt modulating therapeutic molecules for IBD, an understanding of how Wnt signaling may be altered in IBD tissues is required. While earlier work showed altered Wnt pathway gene expression in UC tissues, these studies failed to consider disease conditions (moderate vs severe) and patient treatment history on expression of the Wnt family genes. These previous studies utilized RT-qPCR or microarray and did not reveal how Wnt pathway gene expression might be affected specifically in the epithelium and in the adjacent stromal stem cell niche. Here we report our work investigating expression patterns of Wnt pathway genes in UC biopsies from 12 patients with moderate and severe disease. Patients had either received no anti-TNF treatment or had gone through anti-TNF treatment and partially responded to the treatment. Methods Expression of a set of Wnt pathway genes was assessed in UC colon and rectum biopsies by RNAscope in situ hybridization and compared to expression patterns in normal control colon. The genes included the Wnt target genes AXIN2, LGR5 and RNF43, Wnt ligands and the FZD5 and LRP6 receptors enriched in the intestinal epithelium as well as key Wnt signal modulators RSPO1-4. Results Expression of Wnt target genes were mildly reduced in the UC colon epithelium, while their expression in some crypts appeared much lower. Overall expression levels of Wnt pathway genes did not differ between moderate and severe UC colon and Wnt target gene expression was more affected in the anti-TNF treated colons, which may reflect more refractory disease. Expression of FZD5, LRP6 and the key niche factor RSPO2, was reduced in the UC colon. RSPOs are normally expressed in the stromal cells next to the crypt bottom stem cell compartment but this expression pattern was disrupted in the UC colon as a result of immune cell infiltration. Although expression of Wnts was induced in the UC colon tissues, the location of expression was altered due to tissue damage, potentially making the Wnts less accessible to the intestinal stem cells. Conclusion Reduced expression of Wnt receptors, RSPOs and Wnt target genes indicate insufficient Wnt signal induction in the damaged colon epithelium of UC patients. This suggests that repair of the damaged epithelium by Wnt agonist treatment may constitute a new mechanism of action and benefit patients with UC.

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Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15185 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15185-e15185 ◽

Cited By ~ 1

Author(s):

Carine Bossard ◽

Kevin Chiu ◽

Heekyung Chung ◽

John Duc Nguyen ◽

Emily Creger ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Antitumor Activity ◽

Wnt Signaling ◽

Cell Lines ◽

Wnt Pathway ◽

Pathway Gene ◽

Hct 116

e15185 Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P < .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P< .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).

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