Epidemiological and experimental studies have suggested that deregulated
hepcidin-
ferroportin (FPN) signaling is associated with the increased risk of
cancers. However, the effects of deregulated
hepcidin-FPN signaling on
tumor behaviors such as
metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2
cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop
tumors was also demonstrated in lungs of Hamp1(-/-) mice. Moreover, hepatic
hepcidin deficiency was found to considerably favor
tumor-free survival in Hamp1(-/-) mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic
hepcidin in promoting
lung cancer cell homing and fostering
tumor progression. To explore the role of FPN in regulating
tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by
doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded
tumor growth and
metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine
DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and
vimentin. Additionally, there was also a reduction of
lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the
hepcidin-FPN signaling in modulating
tumor growth and
metastasis, providing new evidence to understand the contribution of this signaling in
cancers.