Functional annotation of IFN-alpha-stimulated gene expression profiles from sensitive and resistant renal cell carcinoma cell lines.
The antiproliferative, antiviral, and immunomodulatory properties of interferons (IFNs) have led to its therapeutic implementation. IFNs effects are mediated by a complex network of signal transducers, culminating in IFN-stimulated gene (ISG) induction. This complexity leads to diverse clinical responses to IFN, from no response to complete regression of disease. Elucidation of ISG induction patterns is, therefore, essential to understand and maximize its therapeutic potential. To correlate ISG expression profiles with IFN responsiveness, two renal cell carcinoma (RCC) cell lines differing in antiviral and apoptotic response to IFN were treated with IFN-alpha for different times, and expression profiles were analyzed using a customized microarray containing 850 unique putative ISGs. Genes with similar kinetics of induction in both cell lines were clustered and analyzed for gene function. Seven sets of coordinately regulated genes were identified by k-means cluster analysis, and significant functional similarities were identified for five of the seven sets. Strikingly, expression of genes associated with transcription temporally preceded expression of those involved in signal transduction. Enhanced antiviral sensitivity to IFN was coincident with sustained expression of ISGs involved in transcriptional regulation. However, no difference in Stat1 activation was observed between the cell lines. Analysis of ISG expression patterns suggests that subtle differences in transcription profiles contribute to differences in IFN responsiveness.
Holko
Michelle
M
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Williams
Bryan R G
BR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D016898:Interferon-alpha; D050791:STAT Transcription Factors