Molecular signatures of N-nitroso compounds in Caco-2 cells: implications for colon carcinogenesis.

2.50
Hdl Handle:
http://hdl.handle.net/10146/76793
Title:
Molecular signatures of N-nitroso compounds in Caco-2 cells: implications for colon carcinogenesis.
Authors:
Hebels, Dennie G.A.J.; Jennen, Danyel G.J.; Kleinjans, Jos C.S.; de Kok, Theo M.C.M.
Abstract:
N-nitroso compounds (NOC) are genotoxic, carcinogenic to animals, and may play a role in human cancer development. Because the gastro-intestinal tract is an important route of exposure through endogenous nitrosation, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate these genomic responses, we analyzed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1 microM) and N-methyl-N-nitrosurea (MNU, 1 mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100 mM), N-nitrosopiperidine (NPIP, 40 mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 h of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and proinflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP, and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon.
Citation:
Toxicol. Sci. 2009, 108 (2):290-300
Journal:
Toxicological sciences : an official journal of the Society of Toxicology
Issue Date:
Apr-2009
URI:
http://hdl.handle.net/10146/76793
DOI:
10.1093/toxsci/kfp035
PubMed ID:
19221148
Additional Links:
http://toxsci.oxfordjournals.org/cgi/content/full/108/2/290
Type:
Article
Language:
en
ISSN:
1096-0929
Sponsors:
This study was funded by both the European Network of Excellence (FOOD-CT-2005-513943) on Environmental Cancer Risk, Nutrition, and Individual Susceptibility, and by Maastricht University.
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorHebels, Dennie G.A.J.-
dc.contributor.authorJennen, Danyel G.J.-
dc.contributor.authorKleinjans, Jos C.S.-
dc.contributor.authorde Kok, Theo M.C.M.-
dc.date.accessioned2009-08-10T08:33:59Z-
dc.date.available2009-08-10T08:33:59Z-
dc.date.issued2009-04-
dc.identifier.citationToxicol. Sci. 2009, 108 (2):290-300en
dc.identifier.issn1096-0929-
dc.identifier.pmid19221148-
dc.identifier.doi10.1093/toxsci/kfp035-
dc.identifier.urihttp://hdl.handle.net/10146/76793-
dc.description.abstractN-nitroso compounds (NOC) are genotoxic, carcinogenic to animals, and may play a role in human cancer development. Because the gastro-intestinal tract is an important route of exposure through endogenous nitrosation, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate these genomic responses, we analyzed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1 microM) and N-methyl-N-nitrosurea (MNU, 1 mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100 mM), N-nitrosopiperidine (NPIP, 40 mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 h of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and proinflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP, and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon.en
dc.description.sponsorshipThis study was funded by both the European Network of Excellence (FOOD-CT-2005-513943) on Environmental Cancer Risk, Nutrition, and Individual Susceptibility, and by Maastricht University.en
dc.language.isoenen
dc.relation.urlhttp://toxsci.oxfordjournals.org/cgi/content/full/108/2/290en
dc.subjectgene expression profilingen
dc.subjectN-nitroso compoundsen
dc.subjectnitrosamidesen
dc.subjectnitrosaminesen
dc.subjectCaco-2en
dc.subjectcolon carcinogenesisen
dc.subject.meshApoptosis-
dc.subject.meshCaco-2 Cells-
dc.subject.meshCell Cycle-
dc.subject.meshColonic Neoplasms-
dc.subject.meshComet Assay-
dc.subject.meshFlow Cytometry-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGenetic Markers-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshIn Situ Hybridization-
dc.subject.meshNitroso Compounds-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshPhenotype-
dc.subject.meshRNA-
dc.titleMolecular signatures of N-nitroso compounds in Caco-2 cells: implications for colon carcinogenesis.en
dc.typeArticleen
dc.identifier.journalToxicological sciences : an official journal of the Society of Toxicologyen

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