BACKGROUND: Interleukin-27 signaling is mediated by the JAK-STAT pathway via 
activation of STAT1 and STAT3, which have tumor suppressive and oncogenic 
activities, respectively. Epithelial-mesenchymal transition (EMT) and 
angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown 
to have potent anti-tumor activity in various cancer models, the role of IL-27 
in EMT and angiogenesis is poorly understood. In this study, we investigated the 
role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT 
pathways in human non-small cell lung carcinoma (NSCLC) cells.
METHODS: STAT activation following IL-27 exposure was measured in human NSCLC 
cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal 
(N-cadherin, vimentin) markers were assessed by Western blot analysis. 
Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by 
ELISA. Cell motility was examined by an in vitro scratch and transwell migration 
assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were 
used to determine whether both STAT1 and STAT3 are required for IL-27 mediated 
inhibition of EMT and secretion of angiogenic factors.
RESULTS: Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) 
STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of 
epithelial phenotypes, including a decrease in the expression of a 
transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker 
(vimentin) with a reciprocal increase in the expression of epithelial markers, 
3) inhibition of cell migration, and 4) reduced production of pro-angiogenic 
factors. STAT1 inhibition in IL-27-treated cells reversed the IL-27 effect with 
resultant increased expression of Snail, vimentin and the pro-angiogenic 
factors. The inhibition of STAT3 activation had no effect on the development of 
the epithelial phenotype.
CONCLUSION: IL-27 induces mesenchymal to epithelial transition and inhibits the 
production of pro-angiogenic factors in a STAT1-dominant pathway. These findings 
highlight the importance of STAT1 in repressing lung carcinogenesis and describe 
a new anti-tumor mechanism of IL-27.