title: Synergistic Gene Expression Signature Observed in TK6 Cells upon Co-Exposure to UVC-Irradiation and Protein Kinase C-Activating Tumor Promoters.
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.
authors.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.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Glover
authors.affiliation: DuPont Industrial Biosciences, Wilmington, Delaware, United States of America.
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, Delaware, United States of America.
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Markell
authors.affiliation: DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, Delaware, United States of America.
authors.forename: Xing
authors.initials: X
authors.lastname: Han
mesh_terms: D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014466:Ultraviolet Rays
chemical_list: D002273:Carcinogens; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate