antitumor ways of celecoxib in gastric cancer

In silico analyses on the implicit in antitumor mechanismof Celebrex in stomachic malignant neoplastic disease

Runing rubric:antitumorwaysof Celebrex in stomachic malignant neoplastic disease

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Highlights:

Celecoxib suppresses Leukocyte transendothelial migration tract in stomachic malignant neoplastic disease.

Celecoxib suppresses the FAK-PKB/Akt signalling in Focal adhesion tract.

Celecoxib promotes rescue tracts of Lysosome and Other glycan debasement.

Abstraction

Background:Celecoxib is a nonsteroidal anti-inflammatory drug which possesses anticancer effects as a new campaigner therapy for stomachic malignant neoplastic disease. This survey aimed to research the antitumor mechanism of Celebrex in stomachic malignant neoplastic disease with bioinformatic methods.

Methods:The cistron look informations GSE56807 ( stomachic malignant neoplastic disease samples and normal controls ) and GSE54657 ( celecoxib-treated gastric malignant neoplastic disease samples and non-treated stomachic malignant neoplastic disease samples ) were downloaded from GEO. After testing the differentially expressed cistrons ( DEGs ) of the two informations sets with Limma bundle in R linguistic communication severally, the common DEGs were so screened out by calculating the intersection. Consecutive, KEGG pathways enrichment was performed utilizing DAVID online tools. Besides, the Protein-protein Interactions ( PPIs ) of the common DEGs were obtained via mapping the common DEGs to the integrating set of PPI informations from IntAct, DIP, BIND and HPRD databases. Then, the PPI web was constructed utilizing the Cytoscape package.

Consequences:After analyzed, 137 common DEGs were obtained between the two DEG sets of stomachic malignant neoplastic disease samples vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples. The common DEGs were chiefly enriched in the tracts of Lysosome, Other glycan debasement, Focal adhesion and Leukocyte transendothelial migration. Besides, three PPI faculties of the common DEGs were found.

Decisions:Celecoxib might play its antitumor effects in stomachic malignant neoplastic disease potentially by stamp downing Leukocyte transendothelial migration tract and the FAK-PKB/Akt signalling in Focal adhesion pathway, every bit good as by advancing deliverance tracts of Lysosome and Other glycan debasement. However, relevant experiments are needed to corroborate our decision.

Keywords:Celebrex, stomachic malignant neoplastic disease, antitumor mechanism, tract

Introduction

Gastric malignant neoplastic disease is the 5th most common malignant neoplastic disease and the 3rd prima cause of malignant neoplastic disease mortality. Presently, more than 70 % of stomachic malignant neoplastic diseases occur in developing states, among which three East Asiatic states: China, Japan and Korea history for 60 % of entire instances. ( Fock, 2014 ) . The forecast of stomachic malignant neoplastic disease is by and large hapless as stomachic malignant neoplastic disease can easy distribute from the tummy to other parts of human organic structure, peculiarly the liver, lungs, castanetss, liner of the venters and lymph nodes ( Ruddon, 2007 ) , and the 5-year endurance rate for stomachic malignant neoplastic disease is reported to be less than 10 % ( Orditura et al. , 2014 ) . Therefore, researches on the interventions for stomachic malignant neoplastic disease are of great importance.

Treatments for stomachic malignant neoplastic disease include surgery ( Chen et al. , 2013 ) , chemotherapy ( Wagner et al. , 2010 ) , and radiation therapy ( Milano et al. , 2014 ) . New intervention attacks and improved ways of current methods are being studied in clinical tests. Drugs used in stomachic malignant neoplastic disease intervention have included: fluorouracil or its parallel capecitabine, carmustine, mitomycin C, semustine and doxorubicin, every bit good as cisplatin and taxotere, frequently in assorted combinations ( Scartozzi et al. , 2007 ; Wagner et al. , 2006 ; Wagner et al. , 2010 ) . Unfortunately, these interventions for stomachic malignant neoplastic disease have displayed dissatisfactory consequences.

Celecoxib is a authoritative COX-2 ( Cyclooxygenase-2 ) selective nonsteroidal anti-inflammatory drug ( NSAID ) and is used to handle the marks and symptoms of degenerative arthritis, arthritic arthritis and ancylosing spondylitis in patients. Previous epidemiological surveies demonstrated that drawn-out intervention with NSAIDs could cut down the hazards of assorted sorts of malignant neoplastic diseases including stomachic malignant neoplastic disease ( Entezari Heravi et al. , 2011 ; Fischer et al. , 2011 ) . It has besides been reported that Celebrex possessed antineoplastic effects as a new campaigner therapy for stomachic malignant neoplastic disease in old surveies. Kimet Al.suggested that the antitumor effects of Celebrex on stomachic malignant neoplastic disease cells might be partially mediated by down-regulation of Akt, GSK3 & A ; beta ; , FKHR, and up-regulation of caspase-9, in the mitochondrial apoptotic tract ( Kim et al. , 2009 ) . The mechanism affecting cell rhythm apprehension, mitochondrial cytochrome C release and caspase activation was besides proposed by Wanget Al.( Wang et al. , 2013 ) . The impact on E-cadherin, VEGF and microvessel denseness of Celebrex to stamp down the invasion of advanced stomachic malignant neoplastic disease was reported every bit good ( Zhou et al. , 2007 ) . However, its antitumor mechanism remains problematic.

This survey aimed to derive a better understanding about the anticancer mechanism of Celebrex on stomachic malignant neoplastic disease with bioinformatics methods. With the advantage of relevant microarrays, we conducted incorporate cistron look profiling analyses on stomachic malignant neoplastic disease vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples and identified the common Differently Expressed Genes ( DEGs ) . Further pathways enrichment analysis and Protein-protein Interaction ( PPI ) web building were performed to foretell the implicit in mechanism during the intervention.

Materials and Methods

Gene Expression Profiles

The look informations GSE56807 ( Wang et al. , 2014 ) and GSE54657 were downloaded from GEO ( Gene Expression Omnibus ) database ( hypertext transfer protocol: //www.ncbi.nlm.nih.gov/geo/ ) . The informations GSE56807 were based on the GPL5175 [ HuEx-1_0-st ] Affymetrix Human Exon 1.0 ST Array [ transcript ( cistron ) version ] platform including 10 samples: 5 paired of stomachic malignant neoplastic disease vs. normal controls. The informations GSE54657 were based on the GPL6244 [ HuGene-1_0-st ] Affymetrix Human Gene 1.0 ST Array [ transcript ( cistron ) version ] platform including 6 samples: 3 celecoxib-treated AGS ( the homo stomachic epithelial cell line AGS ) samples and 3 control AGS samples, among which the celecoxib-treated AGS samples were harvested after incubated with Celebrex in triplicates for 24 hours.

Datas AcquisitionandDEGs Screening

Gene look profiles ( CEL format ) were analyzed by R linguistic communication ( Team, 2012 ) . These informations were first normalized utilizing the Robust Multichip Averaging ( RMA ) algorithm ( Irizarry et al. , 2003 ) . Limma bundle ( Smyth, 2005 ) in R linguistic communication was applied to place the DEGs. For DEGs between stomachic malignant neoplastic disease samples and normal controls, after t-test was applied, the adj.P-value which was adjusted by Benjamini-Hochberg method ( Benjamini and Hochberg, 1995 ) less than 0.05 were set as threshold. Due to different sensitivenesss of different platforms, for DEGs between celecoxib-treated AGS samples and control AGS samples, P-value without accommodation less than 0.01 was set as the cut-off standard. Then, the common DEGs shared by the two groups of DEGs were screened out.

Pathways Enrichment of DEGs

The pathways enrichment analysis of the common DEGs were carried out with DAVID ( Database for Annotation, Visualization and Integrated Discovery ) ( Dennis Jr et al. , 2003 ) package based on KEGG ( Kyoto Encyclopedia of Genes and Genomes ) tract databases ( Kanehisa and Goto, 2000 ) . P-value less than 0.1 and the cistron count in each tract no less than 2 were set as cut-off standards.

Protein-protein Interaction ( PPI ) Network Construction

With the downloaded PPI information from IntAct ( Kerrien et al. , 2011 ) , DIP ( Xenarios et al. , 2002 ) , BIND ( Bader et al. , 2003 ) and HPRD ( Peri et al. , 2004 ) databases and the probes of Rualet Al.( Rual et al. , 2005 ) , Stelzlet Al.( Stelzl et al. , 2005 ) and Ramaniet Al.( Ramani et al. , 2005 ) , we integrated these PPI informations as a PPI set and mapped the DEGs identified above with this set to accomplish the PPI of the DEGs. Then, the PPI web was gotten by Cytoscape package.

Consequences

DEGs Screening

After analyzed, 5190 DEGs between stomachic malignant neoplastic disease and normal controls every bit good as 540 DEGs between celecoxib-treated stomachic malignant neoplastic disease samples and non-treated stomachic malignant neoplastic disease samples were screened out. Then, 137 common DEGs were obtained by calculating the intersection of the two groups of DEGs. The constellating heatmap of the common DEGs was shown in Figure 1. The two informations sets were based on different platforms, so the look degree of cistrons displayed a immense difference. However, we can still acquire the qualitative decisions from the heatmap that these microarrays were dependable and Celebrex did do a difference during the intervention.

Nerve pathwaies Enrichment Analysis

To research the possible effects of Celebrex on stomachic malignant neoplastic disease cells, the common DEGs were subjected to KEGG tracts enrichment analysis. As shown in Table 1, the common DEGs were chiefly enriched in the tract of Lysosome, Other glycan debasement, Focal adhesion and Leukocyte transendothelial migration, among which F ocal adhesion and Leukocyte transendothelial migration were enriched by DEGs that displayed opposite ordinance way in the two consequences sets of stomachic malignant neoplastic disease vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples. Clustering heatmaps of the common DEGs in the enriched tracts were shown in Figure 2.

Protein-protein Interaction ( PPI ) web

To further look into the implicit in map mechanism of Celebrex in stomachic malignant neoplastic disease, PPI interaction webs of the common DEGs were predicted. As shown in Figure 3, three interaction faculties were found. One faculty contained three nods including EPS8, CFTR and MUC13 ; another contained CSRP1, VCL and ACTN1 ; the last contained GLB1 and NEU1. Among these faculties, the one contained CSRP1, VCL and ACTN1 showed opposite ordinance way in the two consequences sets of stomachic malignant neoplastic disease vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples.

Discussion

To derive penetration into the anticancer mechanism of Celebrex on stomachic malignant neoplastic disease, we consistently analyzed the cistron look profiles with bioinformatics methods. After analyzed, 5190 DEGs between stomachic malignant neoplastic disease and normal controls every bit good as 540 DEGs between celecoxib-treated stomachic malignant neoplastic disease samples and non-treated stomachic malignant neoplastic disease samples were screened out. Then, 137 common DEGs were obtained by calculating the intersection of the two groups of DEGs. The biological maps of the common DEGs were farther explored based on the tracts enrichment informations. Furthermore, the PPI web of the common DEGs was besides identified. These consequences might uncover the anticancer mechanism of Celebrex on stomachic malignant neoplastic disease.

The common DEGs which displayed opposite ordinance way in the two consequences sets of stomachic malignant neoplastic disease vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples visually reflected the impact of Celebrex on stomachic malignant neoplastic disease. The consequence of tracts enrichment analysis showed that Focal adhesion and Leukocyte transendothelial migration were enriched by DEGs with the state of affairs mentioned above. The common DEGs enriched in Focal adhesion tract showed up-regulation in stomachic malignant neoplastic disease and down-regulation after treated with Celebrex. Focal adhesion tract plays indispensable functions in of import biological procedures ( Petit and Thiery, 2000 ) , in which the FAK-PKB/ Akt signalling is important for cell endurance. The up-regulation of FAK-PKB/Akt tract is often found in human malignant neoplastic diseases, while the down-regulation of this tract by drugs can take to programmed cell death of the malignant neoplastic disease cells ( Vara et al. , 2004 ) . This result of our analysis consisted with the researches of Kimet Al.( Kim et al. , 2009 ) and Wanget Al. ( Wang et al. , 2013 ) . Besides, the common DEGs enriched in Leukocyte transendothelial migration tract showed up-regulation in stomachic malignant neoplastic disease and down-regulation after treated with Celebrex. Leukocyte transendothelial migration tract is by and large activated in malignant neoplastic disease, therefore haltering the anti-tumour responses of the host ( Enarsson et al. , 2007 ) . This result of our analysis suggested that Celebrex might besides suppressed Leukocyte transendothelial migration tract to exercise its antitumor effects.

However, tracts of Lysosome and Other glycan debasement were more significantly enriched in this survey. The common DEGs enriched in the two tracts were up-regulated in stomachic malignant neoplastic disease and up-regulated to higher degree after treated with Celebrex. Since tracts of Lysosome and Other glycan debasement are both common ways of katabolism, they might be activated as a deliverance response of the host in malignant neoplastic disease. It was besides reported that lysosome could intercede a manner of cell decease with apoptotic or apoptosis-like characteristics which was called lysosomal cell decease ( Aits and J & A ; auml ; & A ; auml ; ttel & A ; auml ; , 2013 ) . Celecoxib might besides advance this procedure to play anticancer functions during the intervention.

Furthermore, PPI web of the common DEGs were constructed to farther measure into the mechanism anticipation. Nevertheless, merely 3 faculties were found during this analysis likely due to the low count of the common DEGs. The faculty which contained VCL and ACTN1 consisted with the consequences of the tracts enrichment analysis as they were both enriched in important tracts. The important nod in this web, CSRP1 ( Cysteine and glycine-rich protein 1 ) , is a member of the CSRP household of cistrons encoding a group of proteins with LIM sphere which are by and large transcription regulators related to cistron ordinance, cell growing, and bodily distinction ( Weiskirchen and G & A ; uuml ; nther, 2003 ) . The dysregulation of CSRP1 might advance programmed cell death during celecoxib intervention in stomachic malignant neoplastic disease by abnormally modulating VCL and ACTN1. Therefore, the PPI web provided a collateral grounds for the tracts enrichment consequences.

Taken together, we screened out the common DEGs in the two consequences sets of stomachic malignant neoplastic disease vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples. Further bioinformatic analyses including tracts enrichment and PPI web building of the common DEGs were conducted. We propose that Celebrex might play its antitumor effects in stomachic malignant neoplastic disease potentially by stamp downing Leukocyte transendothelial migration tract and the FAK-PKB/Akt signalling in Focal adhesion pathway, every bit good as by advancing deliverance tracts of Lysosome and Other glycan debasement. However, relevant experimental informations are needed to corroborate our decision.

FigureLiteregends

Figure 1. The constellating heatmap ofthe common Differently Expressed Genes ( DEGs)of stomachic malignant neoplastic diseasesamples vs. normal controls andcelecoxib-treated gastric malignant neoplastic diseasesamples Vs.non-treated stomachic malignant neoplastic disease samples.Blue footings: normal controls ; xanthous footings: gastric malignant neoplastic disease samples ; ruddy footings: non-treated AGS samples ; green footings: non-treated AGS samples. Colorss associated with look values are present above the heatmap. Due to different sensitivenesss of different platforms, adj.P-value & A ; lt ; 0.05 in stomachic malignant neoplastic disease samples vs. normal controls and P-value & A ; lt ; 0.01 in celecoxib-treated AGS samples vs. non-treated AGS samples were set as standards.

Figure 2. Clustering heatmaps of the common Differently Expressed Genes ( DEGs ) of stomachic malignant neoplastic disease samples vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples in the significantly enriched tracts.Blue footings: normal controls ; xanthous footings: gastric malignant neoplastic disease samples ; ruddy footings: non-treated AGS samples ; green footings: non-treated AGS samples. Colorss associated with look values are present above the heatmap. P-value & A ; lt ; 0.1 and the cistron count & A ; lt ; 2 were set as cut-off standards.

Figure 3. Protein-protein Network of the common Differently Expressed Genes ( DEGs ) of stomachic malignant neoplastic disease samples vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples.Pink nods represent DEGs and the size of each nod represents its significance. Blue lines represent interactions between the nods.

Tables

Table 1. Significantly enriched tracts of thecommondifferentially expressed cistrons ( DEGs )of stomachic malignant neoplastic disease samples vs. normal controls and celecoxib-treated stomachic malignant neoplastic disease samples vs. non-treated stomachic malignant neoplastic disease samples.

Pathway ID

DEGs

RD

Nerve pathway

Count

P-value

hsa04142

NEU1, GLB1, FUCA1, CLN5, ATP6AP1, CTSD

same

Lysosome

6

0.002834

hsa00511

NEU1, GLB1, FUCA1

same

Other glycan debasement

3

0.007776

hsa04510

THBS1, MYL9, FLNA, ACTN1, VCL, LAMC2,

antonym

Focal adhesion

6

0.026095

hsa04670

MYL9, VCL, ACTN1, CLDN1

antonym

Leukocyte transendothelial migration

4

0.076932

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