An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis

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 tran- sition （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 demon- strated in lungs of Hampl-/- mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hampl-/- mice, compared with wild-type mice. These data thus under- scored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulationg tumor progression, we genetically engi- neered 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, with- out 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 hepci- din-FPN signaling in modulating tumor growth and metastasis, providing new evidence to under- stand the contribution of this signaling in cancers.