Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse embryonic stem (ES) cells exposed to oxidative stress

ABSTRACT: Elevated reactive oxidative species (ROS) may be crucial for cellular transformation and tumor progression. Defining the response of stem cells to ROS is critical to understanding the unique sensitivity of stem cells to ROS-mediated transformation and tumor initiation. We examined both the immediate transcriptional and phospho-proteomic responses of murine ES cells induced by a single brief dose of hydrogen peroxide (H2O2) to create a more complete understanding of cell response to ROS. Experiment Overall Design: Murine ES cells were briefly exposed to low and high dose of H2O2 then allowed to recover for 1 hour in maintenance medium before RNA extraction and MG_U74Av2 microarray hybridization.

ORGANISM(S): Mus musculus

SUBMITTER: Christine Richardson

PROVIDER: E-GEOD-18708 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Aims: We explore the role of elevated O2-:H2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers. Results: We observed that elevated O2-:H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apopotic triggers. We established the ROS Index as a quantitative measure of normalized O2-:H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of CD133- and nestin-expressing neural precursors. Furthermore, we established the Connectivity Map to interrogate a gene signature derived from varied ROS Index for patterns of association with individual patient gene expression in 2 clinical databases. We showed that patients with reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O2-:H2O2-mediated chemosensitivity profiles. Innovation and Conclusion: Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate elevated O2-:H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2-:H2O2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2-:H2O2 ratio as a therapeutic strategy. Total RNA from primary neurosphere culture of brain tumor specimens treated with DPI and DDC as well as non-treated CD133+ and CD133- fractions were compared. Specimens were obtained from 3 patients and replicate arrays were performed for all 3 neurosphere cultures.