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Synergistic Gene Expression Signature Observed in TK6 Cells upon Co-Exposure to UVC-Irradiation and Protein Kinase C-Activating Tumor Promoters.

Glover KP, Chen Z, Markell LK, Han X - PLoS ONE (2015)

Bottom Line: TK6 cells exposed to both TPA and UVC had significantly more genes differentially regulated than the theoretical sum of genes induced by either stress alone, thus indicating a synergistic effect on global gene expression patterns.Further analysis revealed that TPA+UVC co-exposure caused synergistic perturbation of specific genes associated with p53, AP-1 and inflammatory pathways important in carcinogenesis.Here we show a novel gene signature that may represent a synergistic interaction in the tumor microenvironment that is relevant to the mechanisms of chemical induced tumor promotion.

View Article: PubMed Central - PubMed

Affiliation: DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, Delaware, United States of America; Department of Biological Sciences, Cell and Molecular Biology Graduate Program, University of the Sciences, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Activation of stress response pathways in the tumor microenvironment can promote the development of cancer. However, little is known about the synergistic tumor promoting effects of stress response pathways simultaneously induced in the tumor microenvironment. Therefore, the purpose of this study was to establish gene expression signatures representing the interaction of pathways deregulated by tumor promoting agents and pathways induced by DNA damage. Human lymphoblastoid TK6 cells were pretreated with the protein kinase C activating tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and exposed to UVC-irradiation. The time and dose-responsive effects of the co-treatment were captured with RNA-sequencing (RNA-seq) in two separate experiments. TK6 cells exposed to both TPA and UVC had significantly more genes differentially regulated than the theoretical sum of genes induced by either stress alone, thus indicating a synergistic effect on global gene expression patterns. Further analysis revealed that TPA+UVC co-exposure caused synergistic perturbation of specific genes associated with p53, AP-1 and inflammatory pathways important in carcinogenesis. The 17 gene signature derived from this model was confirmed with other PKC-activating tumor promoters including phorbol-12,13-dibutyrate, sapintoxin D, mezerein, (-)-Indolactam V and resiniferonol 9,13,14-ortho-phenylacetate (ROPA) with quantitative real-time PCR (QPCR). Here we show a novel gene signature that may represent a synergistic interaction in the tumor microenvironment that is relevant to the mechanisms of chemical induced tumor promotion.

No MeSH data available.


Related in: MedlinePlus

Network analysis of TPA+UVC gene signature.STRING analysis revealed key sub-network clusters and potential gene level interactions connected to p53, TGFβ, TNF and JUN. Colors represent different subnetworks based on K-means clustering. Edge thickness is representative of confidence in interaction based on database mining, experimental evidence and text mining.
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pone.0139850.g006: Network analysis of TPA+UVC gene signature.STRING analysis revealed key sub-network clusters and potential gene level interactions connected to p53, TGFβ, TNF and JUN. Colors represent different subnetworks based on K-means clustering. Edge thickness is representative of confidence in interaction based on database mining, experimental evidence and text mining.

Mentions: The gene signature was further explored to determine protein interactions using the STRING database [18]. To determine the connections between key pathway nodes revealed previously, we imported p53, TGFβ1, TNF and JUN (co-factor in AP1 transcription factor) into the analysis. STRING analysis revealed 5 interconnected sub-networks in the gene signature including an AP1 cluster (11 genes), a p53 and TGFβ cluster (6 genes), a TNFα cluster (4 genes), an IFNγ cluster (4 genes) and a B-cell transcription factor cluster (3 genes) (Fig 6). Two other sub-networks were also found but not connected to the larger network of protein interactions including a SH3 domain cluster based on protein homology (2 genes) and an uncharacterized cluster with CD14 based on co-expression.


Synergistic Gene Expression Signature Observed in TK6 Cells upon Co-Exposure to UVC-Irradiation and Protein Kinase C-Activating Tumor Promoters.

Glover KP, Chen Z, Markell LK, Han X - PLoS ONE (2015)

Network analysis of TPA+UVC gene signature.STRING analysis revealed key sub-network clusters and potential gene level interactions connected to p53, TGFβ, TNF and JUN. Colors represent different subnetworks based on K-means clustering. Edge thickness is representative of confidence in interaction based on database mining, experimental evidence and text mining.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592187&req=5

pone.0139850.g006: Network analysis of TPA+UVC gene signature.STRING analysis revealed key sub-network clusters and potential gene level interactions connected to p53, TGFβ, TNF and JUN. Colors represent different subnetworks based on K-means clustering. Edge thickness is representative of confidence in interaction based on database mining, experimental evidence and text mining.
Mentions: The gene signature was further explored to determine protein interactions using the STRING database [18]. To determine the connections between key pathway nodes revealed previously, we imported p53, TGFβ1, TNF and JUN (co-factor in AP1 transcription factor) into the analysis. STRING analysis revealed 5 interconnected sub-networks in the gene signature including an AP1 cluster (11 genes), a p53 and TGFβ cluster (6 genes), a TNFα cluster (4 genes), an IFNγ cluster (4 genes) and a B-cell transcription factor cluster (3 genes) (Fig 6). Two other sub-networks were also found but not connected to the larger network of protein interactions including a SH3 domain cluster based on protein homology (2 genes) and an uncharacterized cluster with CD14 based on co-expression.

Bottom Line: TK6 cells exposed to both TPA and UVC had significantly more genes differentially regulated than the theoretical sum of genes induced by either stress alone, thus indicating a synergistic effect on global gene expression patterns.Further analysis revealed that TPA+UVC co-exposure caused synergistic perturbation of specific genes associated with p53, AP-1 and inflammatory pathways important in carcinogenesis.Here we show a novel gene signature that may represent a synergistic interaction in the tumor microenvironment that is relevant to the mechanisms of chemical induced tumor promotion.

View Article: PubMed Central - PubMed

Affiliation: DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, Delaware, United States of America; Department of Biological Sciences, Cell and Molecular Biology Graduate Program, University of the Sciences, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Activation of stress response pathways in the tumor microenvironment can promote the development of cancer. However, little is known about the synergistic tumor promoting effects of stress response pathways simultaneously induced in the tumor microenvironment. Therefore, the purpose of this study was to establish gene expression signatures representing the interaction of pathways deregulated by tumor promoting agents and pathways induced by DNA damage. Human lymphoblastoid TK6 cells were pretreated with the protein kinase C activating tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and exposed to UVC-irradiation. The time and dose-responsive effects of the co-treatment were captured with RNA-sequencing (RNA-seq) in two separate experiments. TK6 cells exposed to both TPA and UVC had significantly more genes differentially regulated than the theoretical sum of genes induced by either stress alone, thus indicating a synergistic effect on global gene expression patterns. Further analysis revealed that TPA+UVC co-exposure caused synergistic perturbation of specific genes associated with p53, AP-1 and inflammatory pathways important in carcinogenesis. The 17 gene signature derived from this model was confirmed with other PKC-activating tumor promoters including phorbol-12,13-dibutyrate, sapintoxin D, mezerein, (-)-Indolactam V and resiniferonol 9,13,14-ortho-phenylacetate (ROPA) with quantitative real-time PCR (QPCR). Here we show a novel gene signature that may represent a synergistic interaction in the tumor microenvironment that is relevant to the mechanisms of chemical induced tumor promotion.

No MeSH data available.


Related in: MedlinePlus