Wnt Pcp Signaling Pathway And Human Cancer Review Pdf Software
File Name: wnt pcp signaling pathway and human cancer review software.zip
- Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression.
- Targeting the Wnt signalling pathway in cancer: prospects and perils
- Role of DKK4 in Tumorigenesis and Tumor Progression
Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity PCP pathway and inhibition of the canonical Wnt signaling branch. Editor: John D.
Metrics details. Over the past few years, microRNAs miRNAs have not only emerged as integral regulators of gene expression at the post-transcriptional level but also respond to signalling molecules to affect cell function s. Furthermore, the fundamental understanding of miRNA-mediated regulation of Wnt-signalling pathway and vice versa has been significantly improved by high-throughput genomics and bioinformatics technologies. Whilst, these approaches have identified a number of specific miRNA s that function as oncogenes or tumour suppressors, additional analyses will be necessary to fully unravel the links among conserved cellular signalling pathways and miRNAs and their potential associated components in cancer, thereby creating therapeutic avenues against tumours. The Wnt pathway is a highly regulated signalling pathway that controls numerous stages of animal development and tissue homeostasis.
Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression.
Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity PCP pathway and inhibition of the canonical Wnt signaling branch. Editor: John D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing interests: The authors have declared that no competing interests exist. Lung cancer is the leading cause of cancer-related death in both men and women throughout the world, and more than fifteen thousand people in the United States die from the disease each year .
SCC is characterized as a poorly differentiated tumor subtype that develops in the proximal airways and is strongly associated with cigarette smoking.
In contrast, AC usually arises in the peripheral airways and is more commonly observed in non-smokers and women. High-throughput gene expression analysis has been widely used to study cancer to facilitate the discovery of novel oncogenes and elucidate the mechanism of tumorigenesis. These genome-wide analyses usually result in the identification of hundreds or thousands of genes with an altered expression pattern.
However, interpreting the relevance of these long gene lists remains a significant challenge  , . Several pathway analysis approaches have been developed to uncover the molecular signaling patterns underlying these candidate gene lists.
One of the most common approaches is based on statistical enrichment e. These methods test the gene list of interest for enrichment relative to groups of genes that are known to share a common function. This approach, broadly referred to here as functional group enrichment analysis FGA , calculates the statistical significance of the overlap with the goal of identifying activated or repressed pathways.
These tools have been successfully applied to generate molecular insights in many biological systems. In this study, we analyzed a collection of lung cancer samples using an FGA approach with the goal of defining the active pathways that differentiate the two major sample groups. While developmental and cell cycle pathways were broadly implicated, this approach was unable to identify specific molecular pathways that were amenable to hypothesis testing.
This algorithm specifically accounts for the case where dysregulation of even a single pathway member can result in altered pathway signaling. Further characterization of these samples revealed an inhibition of the canonical branch of the Wnt pathway, coupled with an enhancement of the non-canonical Wnt PCP signaling cascade. These results suggest that lung SCC uses an alternate branch of the Wnt pathway for survival and development. Probe sets with a maximum intensity below were removed.
Hierarchical clustering was performed with R using a Euclidean distance metric and average linkage. The significance of differential expression for each gene was evaluated using the two primary clusters from the global clustering analysis. Functional gene sets were downloaded from two sources.
The p-value for the enrichment of a gene set of N G genes and a functional group of N F genes was calculated by: 1. Where N C is defined as the number of genes within the gene set assigned to the functional group, N T is the total number of annotated genes of microarray. The FGA approach is also illustrated schematically in Figure 1. FDR was estimated using the Benjamini-Hochberg method, and a threshold of 0. Red boxes indicate dysregulation of a specific gene in a specific sample.
FGA approaches employ a three-step process. In step 1, differentially expressed genes are identified, typically based on a t-test or ANOVA analysis. In step 2, genes with a role the FGS of interest are identified. CAFET employs a similar four-step process. In step 1, FGS genes are first identified and the corresponding sub-matrix is extracted. In step 2, samples are evaluated for the presence of a particular gene expression signature.
In this study, the signature is marked as present if one or more pathway genes are dysregulated. In step 3, the division of samples between two groups of interest is defined. CAFET calculates the degree to which samples with a desired expression property were concentrated in a particular sample cluster.
In this study, the desired property for a single gene in a single sample was its overexpression relative to the median expression across all samples. Our expression filtering criterion focused on expression greater than 2. Asymmetric thresholds were used because the baseline noise limits the magnitude of down-regulation. For any gene with multiple probes, all those samples with at least one probe reaching the criteria were taken into account. FDR was again estimated using the Benjamini-Hochberg method, and a threshold of 0.
In the latter case, the desired property is overexpression of any gene in the functional group illustrated schematically in Figure 1. FDR was then estimated as described previously. Only functional groups with at least 5 genes with were considered.
To assess the degree to which individual samples exhibited dysregulation of the Wnt pathway, we developed an ad hoc scoring function based on gene expression values. A normalized expression value is calculated for each gene based on the average intensity of all its probes after log2 transformation and standardization. The score of the Wnt SCC signature for any sample is the sum of expression values of upregulated genes subtracting the sum of expression values of down-regulated genes.
Informed consent was obtained from patients by Asterand under approval from the appropriate IRBs. Hierarchical clustering separated the majority of the samples into two branches, which we labeled as simply Group 1 and Group 2.
Group 2 was further subdivided into Group 2a, which contained only AC samples, and Group 2b, which contained the majority of the remaining SCC samples that were not found in Group 1 Figure 2. Recognizing that lung cancer is a very heterogeneous disease even within histological classes, we specifically chose to use the global, unsupervised clustering results as the basis for our study.
Specifically, we focused on identifying the molecular basis distinguishing Group 1 from Group 2 lung cancer samples. Hierarchical clustering was performed based on log-transformed expression data using Euclidean distance and average linkage.
Group 2 was further subdivided into Group 2a dark blue and Group 2b red. We identified genes with significantly higher expression in Group 1 Table S1 , and genes with significantly higher expression in Group 2 Table S2.
To identify relevant pathways in these gene lists, we applied FGA analysis to these sets of genes. We found that genes overexpressed in Group 1 were enriched in functional groups related to cell cycle and development Table S3 , while genes overexpressed in Group 2 had significant association with many immune response functional groups Table S4.
Enrichment in functional groups related to cell cycle and development was expected given their known roles in oncogenesis and metastasis. However, the functional gene groups identified in this analysis often contained hundreds or thousands of genes, and as a result, the formulation of specific mechanistic hypotheses proved difficult. Enrichment scores of more specific signaling pathways using FGA were not statistically significant, and varying filtering criteria for differential expression did not result in any improvement.
We hypothesized that this lack of specificity was a fundamental property of the enrichment analysis underlying FGA. Specifically, the FGA approach is designed to detect pathways in which multiple pathway genes are differentially expressed, and more significant p-values are achieved when more pathway genes are differentially expressed Figure 1. The second step involves identifying the set of pathway genes for a pathway of interest, and third step tests the enrichment of pathway genes among differentially expressed genes.
This procedure is quite effective when the majority of pathway genes are differentially expressed in each case sample studied Figure 1A. However, dysregulation of even a single pathway gene is often sufficient to result in altered pathway signaling. Consider a study in which all case samples have altered pathway activity, but where each sample has a different pathway member dysregulated Figure 1B.
In this case, FGA will not detect the importance of the altered pathway. In the first step, data for pathway members are extracted from the gene expression matrix. In the second key step, CAFET identifies samples with a relevant gene expression signature, which in our case can be defined by the dysregulation of as few as one pathway member.
The third step defines the clinically relevant sample groups e. The CAFET procedure is sensitive to data sets in which the majority of pathway members are dysregulated Figure 1A , as well less obvious cases in which only one or a few pathway members are dysregulated Figure 1B. In contrast to FGA where more significant p-values are achieved when more pathway genes are differentially expressed, CAFET reports more significant p-values when more samples have at least one differentially expressed pathway member.
As designed, this list also included specific enriched molecular pathways. Sixty of these ninety samples were found to cluster with Group 1, indicating a strong association of the Wnt pathway. Given the known roles for Wnt signaling in oncogenesis and metastasis, we focused our study on the Wnt pathway to further investigate its potential dysregulation in the two main NSCLC subtypes  , .
We first expanded our list of Wnt pathway members to genes in nine Wnt-related functional groups Tables S7 and S8 , and then applied CAFET on a gene-by-gene basis, testing whether samples with substantially altered expression were enriched among the SCC-dominated Group 1.
This approach identified 53 genes that displayed differential expression and could be associated specifically with the Group 1 cluster Table 2. Of these 53 genes, 34 were observed to be strongly up-regulated in Group 1, while 19 displayed significantly reduced expression levels.
SOX2 has recently been identified as a lineage survival oncogene in lung and esophageal squamous carcinoma  — . Several of these findings are summarized here:. The three branches of Wnt signaling are shown —calcium pink background , beta-catenin green background , and PCP blue background. Genes whose expression change is consistent with canonical pathway inhibition and PCP pathway activation are colored red.
Those genes promoting canonical signaling and inhibiting the PCP branch are colored green. Genes with no significant change in expression, or whose expression change has no selectivity between the canonical and non-canonical branches are colored white.
Both of these Wnt ligands are known to enhance the non-canonical branch of the Wnt pathway while inhibiting the canonical signaling cascade. Similarly all nine samples overexpressing WNT11 were Group 1 samples. This gene was reported to repress canonical Wnt signaling  ,  and to activate the non-canonical Wnt pathway . The LRP6 co-receptor is required for canonical Wnt signaling, but not non-canonical signaling  , .
This gene functions as a switch by enhancing canonical Wnt signaling while inhibiting non-canonical Wnt signaling  , . Among all the changes in the Wnt pathway, there were only three changes that specifically indicated a potential activation in canonical signaling: increased expression of WNT2B , and the down-regulation of FRZB and SKP1  , .
In contrast, 12 of the observed changes were consistent with the activation of the non-canonical Wnt pathway or inhibition of the canonical signaling branch.
To test the generality of these findings, we examined the role of the Wnt pathway in multiple independent data sets. Each column represents one of the lung cancer samples as ordered in Fig 1.
SCC samples are colored brown and AC samples are colored blue. Each row represents a Wnt pathway gene in Table 2 , ranked according to p-value. Red and blue cells indicate overexpression and down-regulation, respectively, of individual genes in specific samples.
Targeting the Wnt signalling pathway in cancer: prospects and perils
International Journal of Medical Sciences. Journal of Cancer. Journal of Genomics. Global reach, higher impact. Journal of Genomics - Submit manuscript now Int J Biol Sci ; 14 3
This is an open access article distributed under the terms of Creative Commons Attribution License. Human cervical carcinoma is one of the most preventable cancer types in women. Therefore, it is critical to explore and understand the mechanisms concerning the development and metastasis of cervical cancer, which may help us impede cervical cancer progression. CTHRC1 is an extracellular matrix protein that is associated with atherosclerosis 2. Recently, CTHRC1 was found to be upregulated during the tumorigenesis and metastasis of certain cancers 3 and promoted cancer cell invasion and migration 4 — 6. Recently, studies have suggested that Cthrcl may activated the non-canonical planar cell polarity PCP pathway, one of the 3 Wnt signaling pathways.
Role of DKK4 in Tumorigenesis and Tumor Progression
Representing these intricate signaling mechanisms through bioinformatic approaches is challenging. Nevertheless, a simplified but reliable bioinformatic WNT pathway model is needed, which can be further utilized to decipher specific WNT activation states within e. In order to build such a model, we collected, parsed, and curated available WNT signaling knowledge from different pathway databases.
Shaw Holly V. The Wnt pathway, involved in cancer development and progression, has for a long time been said to be undruggable, owing to its complexity and involvement in stem cell biology. This mindset has shifted in the last few years as new research and insights into the pathway mechanisms specific to tumour cells become apparent, leading to the development of multiple compounds targeting the pathway.
Обернувшись, они увидели быстро приближавшуюся к ним громадную черную фигуру. Сьюзан никогда не видела этого человека раньше. Подойдя вплотную, незнакомец буквально пронзил ее взглядом. - Кто это? - спросил. - Сьюзан Флетчер, - ответил Бринкерхофф.
Странно. Я вчера говорил с. Велел ему сегодня не приходить. Он ничего не сказал о том, что поменялся с тобой дежурством. У Чатрукьяна ком застрял в горле. Он молчал. - Ну ладно, - вздохнул Стратмор.
Итальянец засмеялся. Он явно не верил своим ушам. - Dov'ela plata. Где деньги. Беккер достал из кармана пять ассигнаций по десять тысяч песет и протянул мотоциклисту.
Однако когда настало время загрузки программного обеспечения, персоналу, работавшему с ТРАНСТЕКСТОМ, объявили, что планы изменились. В связи с чрезвычайной обстановкой, в которой обычно осуществляется антитеррористическая деятельность АНБ, ТРАНСТЕКСТ станет независимым инструментом дешифровки, использование которого будет регулироваться исключительно самим АНБ. Энсей Танкадо был возмущен.
Коммандер! - из последних сил позвала Сьюзан. Хейл развернул Сьюзан в ту сторону, откуда слышался голос Стратмора. - Выстрелишь - попадешь в свою драгоценную Сьюзан.
Сьюзан сообщила Дэвиду, что ее работа заключается в изучении шифров, взламывании их ручными методами и передаче расшифрованных сообщений руководству. Но это было не совсем. Сьюзан переживала из-за того, что ей пришлось солгать любимому человеку, но у нее не было другого выхода. Все, что она сказала, было правдой еще несколько лет назад, но с тех пор положение в АН Б изменилось.
Но, приглядевшись, он убедился, что она вовсе не такая изысканная особа, как ему показалось вначале. Веки припухли, глаза красные, левая рука у локтя - вся в кровоподтеках с синеватым отливом. Господи Иисусе, - подумал .