Under normal physiological conditions, STAT3 activity is tightly controlled; however, intracellular signaling pathways involving STAT3 are frequently constitutively activated in many different human primary tumors . We and others have shown that constitutive activation of STAT3 371935-74-9 provides cancer cells with growth and survival advantages and enhances tumor angiogenesis and metastasis . Recent studies have also indicated that STAT3 activation contributes to tumor immune evasion . These findings indicate that aberrant STAT3 signaling affects a wide variety of fundamental cellular functions through multiple mechanisms. To date, up-regulated expression of numerous STAT3 target genes has been identified, including VEGF , Bcl-2, Bcl-xL , p21, Cyclin D1 and survivin . These STAT3 target genes have generally been identified on an individual basis, while few studies have attempted to identify large numbers of STAT3 regulated genes . We took a broad approach to identify novel STAT3 regulated genes involved in oncogenesis by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-active STAT3. Combining this approach with computational analysis of the microarray results, we were able to define the gene expression profile of cells expressing activated STAT3 and examine the role of STAT3 in both positive and negative regulation of gene expression. Pathway and functional analysis demonstrate that STAT3 has an important role in regulating, both positively and negatively, a diverse array of cellular processes in addition to transcription. STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. These include genes involved in cell adhesion, cytoskeletal remodeling, nucleotide, lipid and protein metabolism, as well as signal transduction. Through computational analysis of our data, we identified Necdin, a negative growth regulator, as a novel potential STAT3 target gene. Necdin is a potent growth suppressor that is predominantly expressed in post-mitotic neurons . Necdin expression has been shown to be down-regulated in both carcinoma cell lines and primary tumors , suggesting that repression of Necdin expression may have a role in oncogenesis.