Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated in diverse human tumors and may play a direct role in malignant transformation. However, the full complement of target genes that STAT3 regulates to promote oncogenesis is not known. We created a system to express a constitutively active form of STAT3, STAT3-C, in mouse fibroblasts and used it to identify STAT3 targets. We showed that a subset of these targets, which include transcription factors regulating cell growth, survival, and differentiation, are coexpressed in a range of human tumors. Using immunohistochemical staining of tissue microarrays, we showed that these targets are enriched in breast and prostate tumors harboring activated STAT3. Finally, we showed that STAT3 is required for the expression of these genes in a breast cancer cell line. Taken together, these results identify a cohort of STAT3 targets that may mediate its role in oncogenesis.
Highlights
Several transcription factors are inappropriately activated in human tumors and capable of transforming cell lines in vitro
Expression of signal transducer and activator of transcription 3 (STAT3)-C is sufficient for transformation of these cells and provides a good system to identify targets of STAT3 involved in oncogenesis [4]
The magnitude of STAT3-Cmediated target gene induction was similar to the magnitude of IL-6- and OSM-mediated gene induction, suggesting that STAT3-C was acting at physiologic levels
Summary
Several transcription factors are inappropriately activated in human tumors and capable of transforming cell lines in vitro. These oncogenic transcription factors function by activating or repressing target genes that collaborate to promote cell survival and proliferation. Accumulating evidence suggests that signal transducer and activator of transcription 3 (STAT3), a member of the STAT family of proteins, is such an oncogene. STAT3 is activated by phosphorylation on a tyrosine residue in its COOH terminus; this phosphorylation is followed by dimerization, nuclear translocation, DNA binding, and transcriptional activation of STAT3 target genes. Several human cancers, including breast cancer, prostate cancer, and head and neck cancer, and several hematologic malignancies, including acute myelogenous leukemia and multiple myeloma, contain persistently tyrosinephosphorylated STAT3 [1]. STAT3 is necessary for v-src transformation of fibroblasts, and a constitutively active mutant of STAT3 is sufficient to transform fibroblasts [2,3,4]
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