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Abstract
Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin.
Highlights
STAT3 is a latent cytoplasmic transcription factor, induced by a variety of upstream signals, including growth factors, cytokines and non-receptor tyrosine kinases [1,2,3,4,5,6,7]
With this approach we were able to confirm differential expression of several previously identified STAT3 target genes, as well as a novel target gene, with a wide range of biological functions and roles in multiple cellular pathways. These results suggest that STAT3 has a wider impact on cellular processes than demonstrated to date and that STAT3 acts as a central coordinator of its own cellular signaling pathways
Few other genes have been identified to date that are negatively regulated by STAT3
Summary
STAT3 is a latent cytoplasmic transcription factor, induced by a variety of upstream signals, including growth factors, cytokines and non-receptor tyrosine kinases [1,2,3,4,5,6,7]. We and others have shown that constitutive activation of STAT3 provides cancer cells with growth and survival advantages [16] and enhances tumor angiogenesis [17] and metastasis [18]. Recent studies have indicated that STAT3 activation contributes to tumor immune evasion [19,20]. These findings indicate that aberrant STAT3 signaling affects a wide variety of fundamental cellular functions through multiple mechanisms
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