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

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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TEAD2, a Hippo pathway gene, is somatically mutated in gastric and colorectal cancers with high microsatellite instability

Apmis ◽

10.1111/apm.12327 ◽

2014 ◽

Vol 123 (4) ◽

pp. 359-360 ◽

Cited By ~ 2

Author(s):

Eun Mi Je ◽

Youn Jin Choi ◽

Yeun Jun Chung ◽

Nam Jin Yoo ◽

Sug Hyung Lee

Keyword(s):

Microsatellite Instability ◽

Hippo Pathway ◽

Colorectal Cancers ◽

Pathway Gene

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Wnt Pathway Gene Expression Is Associated With Arterial Stiffness

Journal of the American Heart Association ◽

10.1161/jaha.119.014170 ◽

2020 ◽

Vol 9 (3) ◽

Cited By ~ 1

Author(s):

Allison L. Kuipers ◽

Iva Miljkovic ◽

Emma Barinas‐Mitchell ◽

Cara S. Nestlerode ◽

Ryan K. Cvejkus ◽

...

Keyword(s):

Gene Expression ◽

Arterial Stiffness ◽

Pulse Wave Velocity ◽

Wave Velocity ◽

Wnt Pathway ◽

Pulse Wave ◽

Glycogen Synthase ◽

African Ancestry ◽

Wnt Signaling Pathway ◽

Pathway Gene

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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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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Differential transcriptional profile of the Wnt pathway in sporadic colorectal cancers with and without microsatellite instability

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)71227-8 ◽

2008 ◽

Vol 6 (9) ◽

pp. 13-14

Author(s):

P. Ortega ◽

A. Morán ◽

C. De Juan ◽

C. Frías ◽

T. Fernández-Marcelo ◽

...

Keyword(s):

Microsatellite Instability ◽

Wnt Pathway ◽

Transcriptional Profile ◽

Colorectal Cancers

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Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003414 ◽

2021 ◽

Vol 9 (12) ◽

pp. e003414

Author(s):

Jung Ho Kim ◽

Mi-Kyoung Seo ◽

Ji Ae Lee ◽

Seung-Yeon Yoo ◽

Hyeon Jeong Oh ◽

...

Keyword(s):

Gene Expression ◽

Microsatellite Instability ◽

Molecular Subtype ◽

Colorectal Cancers ◽

Molecular Characteristics ◽

Immune Parameters ◽

Whole Exome ◽

Tumor Mutational Burden ◽

Consensus Molecular Subtype

BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.

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