STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction pathway and well described for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, STAT2 is unique as IFNs are the only cytokines known to date to induce its activation. Given the inflammatory and antiproliferative dual nature of IFNs, our initial hypothesis was that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory microenvironment. In contradiction to our hypothesis, deletion of STAT2 inhibited rather than promoted AOM/DSS-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. This protective effect was not restricted to the colon as deletion of STAT2 also inhibited DMBA/TPA-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of proinflammatory mediators. Deletion of STAT2 decreased AOM/DSS-induced expression and release of proinflammatory mediators such as interleukin 6 and CCL2 and decreased interleukin-6 release from skin carcinoma cells, which in turn decreased STAT3 activation. Therefore, our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of proinflammatory mediators, which then activate the oncogenic STAT3 signaling pathway.

This talk is also presented as Poster A27.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-02.