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| Status |
Public on Aug 02, 2012 |
| Title |
Suppression of IFN-induced transcription underlies IFN defects generated by activated Ras/MEK in human cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Certain oncolytic viruses exploit activated Ras signalling in order to replicate in cancer cells. Constitutive activation of the Ras/MEK pathway is known to suppress the effectiveness of the interferon (IFN) antiviral response, which may contribute to Ras-dependent viral oncolysis. Here, we identified 10 human cancer cell lines (out of 16) with increased sensitivity to the anti-viral effects of IFN-α after treatment with the MEK inhibitor U0126, suggesting that the Ras/MEK pathway underlies their reduced sensitivity to IFN. To determine how Ras/MEK suppresses the IFN response in these cells, we used DNA microarrays to compare IFN-induced transcription in IFN-sensitive SKOV3 cells, moderately resistant HT1080 cells, and HT1080 cells treated with U0126. We found that 267 genes were induced by IFN in SKOV3 cells, while only 98 genes were induced in HT1080 cells at the same time point. Furthermore, the expression of a distinct subset of IFN inducible genes, that included RIGI, GBP2, IFIT2, BTN3A3, MAP2, MMP7 and STAT2, was restored or increased in HT1080 cells when the cells were co-treated with U0126 and IFN. Bioinformatic analysis of the biological processes represented by these genes revealed increased representation of genes involved in the anti-viral response, regulation of apoptosis, cell differentiation and metabolism. Furthermore, introduction of constitutively active Ras into IFN sensitive SKOV3 cells reduced their IFN sensitivity and ability to activate IFN-induced transcription. This work demonstrates for the first time that activated Ras/MEK in human cancer cells induces downregulation of a specific subset of IFN-inducible genes.
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| Overall design |
HT1080 cancer cells treated for 6 hours or 12 hours with interferon-alpha (500U/ml), the MEK inhibitor U0126 (20uM) or both, triplicate biological samples (18 samples). SKOV3 cells treated with interferon-alpha (500U/ml) for 6h, triplicate biological samples (6 samples).
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| Contributor(s) |
Christian SL, Zu D, Licursi M, Komatsu Y, Pongnopparat T, Codner DA, Hirasawa K |
| Citation(s) |
22970192 |
| Submission date |
Jul 28, 2011 |
| Last update date |
Jul 26, 2018 |
| Contact name |
Sherri L Christian |
| E-mail(s) |
sherri@mun.ca
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| Phone |
(709)864-8550
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| Organization name |
Memorial University of Newfoundland
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| Department |
Biochemistry
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| Street address |
232 Elizabeth Ave
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| City |
St. John's |
| State/province |
Newfoundland |
| ZIP/Postal code |
A1B3X9 |
| Country |
Canada |
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| Platforms (1) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (30)
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| GSM768614 |
HT1080, control, 12h, rep1 |
| GSM768615 |
HT1080, control, 12h, rep2 |
| GSM768616 |
HT1080, control, 12h, rep3 |
| GSM768617 |
HT1080, IFN, 6h, rep1 |
| GSM768618 |
HT1080, IFN, 6h, rep2 |
| GSM768619 |
HT1080, IFN, 6h, rep3 |
| GSM768620 |
HT1080, IFN, 12h, rep1 |
| GSM768621 |
HT1080, IFN, 12h, rep2 |
| GSM768622 |
HT1080, IFN, 12h, rep3 |
| GSM768623 |
HT1080, U0126, 6h, rep1 |
| GSM768624 |
HT1080, U0126, 6h, rep2 |
| GSM768625 |
HT1080, U0126, 6h, rep3 |
| GSM768626 |
HT1080, U0126, 12h, rep1 |
| GSM768627 |
HT1080, U0126, 12h, rep2 |
| GSM768628 |
HT1080, U0126, 12h, rep3 |
| GSM768629 |
HT1080, IFN+U0126, 6h, rep1 |
| GSM768630 |
HT1080, IFN+U0126, 6h, rep2 |
| GSM768631 |
HT1080, IFN+U0126, 6h, rep3 |
| GSM768632 |
HT1080, IFN+U0126, 12h, rep1 |
| GSM768633 |
HT1080, IFN+U0126, 12h, rep2 |
| GSM768634 |
HT1080, IFN+U0126, 12h, rep3 |
| GSM768635 |
SKOV3, control, 6h, rep1 |
| GSM768636 |
SKOV3, control, 6h, rep2 |
| GSM768637 |
SKOV3, control, 6h, rep3 |
| GSM768638 |
SKOV3, IFN, 6h, rep1 |
| GSM768639 |
SKOV3, IFN, 6h, rep2 |
| GSM768640 |
SKOV3, IFN, 6h, rep3 |
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| Relations |
| BioProject |
PRJNA144923 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE31019_RAW.tar |
131.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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