Abstract 2123: Cytoplasmic STAT1 expression level opposes disease-specific survival of sarcoma patients

Signal Transducer and Activator of Transcription 1 (STAT1) is a key mediator in the interferon gamma (IFN-γ) signaling pathway. It is well known that IFN-γ-activated STAT1 (pSTAT1) plays a critical role in the suppression of tumor development. However, STAT1 has also been shown to act as a tumor promoter in certain types of cancers. These findings indicate that STAT1 harbors dual functionality, functioning as either a tumor suppressor, or a promoter, a distinction that may ultimately depend on the tumor microenvironment. In this study, we hypothesized that the distribution of STAT1 (cytoplasmic vs nuclear) could affect disease-specific survival of sarcoma patients. STAT1 protein expression levels were examined in 123 soft tissue sarcoma samples from human patients by immunohistochemical staining. We observed a positive correlation between the nuclear STAT1 (pSTAT1) protein level and disease-specific survival. A statistically significant inverse correlation was also observed between the cytoplasmic STAT1 protein level and disease-specific survival in sarcoma patients. We have shown that STAT1 is negatively regulated by an interferon-stimulated gene, Interferon Regulatory Factor 8 (IRF8). Disruption of IRF8 function by ectopic expression of an IRF8 dominant negative mutant resulted in dramatic up-regulation of STAT1, down-regulation of Janus kinase 1 (JAK1) and pSTAT1, and increased metastatic potential of sarcoma cells in an experimental metastasis mouse model. In addition, using microRNA microarray analysis we have identified a possible mechanism for these changes through mi106b. The possibility of cytoplasmic STAT1 and nuclear STAT1 accumulation being responsible for the observed difference in disease-specific survival of sarcoma patients merits further study of the role STAT1's localization plays in cancer progression. Direct evidence of cytoplasmic STAT1 increasing tumor cell survival, as well as confirmation of our proposed mechanism for STAT1 regulation through IRF8 is still needed. Taken together, our research suggests that IRF8 is a negative regulator of cytoplasmic STAT1 and STAT1 is indeed a tumor promoter. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2123. doi:10.1158/1538-7445.AM2011-2123