dateReleased: |
08-31-2013
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description: |
K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the 'Ras-addiction' of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells. The si-Ctrl, si-Med23 and si-Elk1 A549 cells were cultured in the normal condition. Then the cells were harvested for RNA extraction and hybridization on Affymetrix microarrays. The analysis contain 9 samples. si-Ctrl cells have three replicates (si-Ctrl#1, si-Ctrl#2 and si-Ctrl#3), and the si-Med23 or si-Elk1 group contains three different cell lines that harbor three different RNAi oligos against Med23 or Elk1 (si-Med23A, B, C and si-Elk1A, B, C).
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privacy: |
not applicable
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aggregation: |
instance of dataset
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ID: |
E-GEOD-40517
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refinement: |
raw
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alternateIdentifiers: |
40517
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keywords: |
functional genomics
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dateModified: |
08-19-2015
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availability: |
available
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types: |
gene expression
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name: |
Homo sapiens
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ID: |
A-AFFY-44
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name: |
Affymetrix GeneChip Human Genome U133 Plus 2.0 [HG-U133_Plus_2]
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accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-40517/E-GEOD-40517.raw.1.zip |
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ArrayExpress
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gzip compressed
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none
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accessURL: | https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-40517/E-GEOD-40517.processed.1.zip |
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gzip compressed
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format: |
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accessType: |
download
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authentication: |
none
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none
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accessURL: | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE40517 |
storedIn: |
Gene Expression Omnibus
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not compressed
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format: |
HTML
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accessType: |
landing page
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primary: |
true
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authentication: |
none
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none
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abbreviation: |
EBI
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homePage: | http://www.ebi.ac.uk/ |
ID: |
SCR:004727
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name: |
European Bioinformatics Institute
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homePage: | https://www.ebi.ac.uk/arrayexpress/ |
ID: |
SCR:002964
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name: |
ArrayExpress
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